Thromboxane A2 receptor antagonists.

Thromboxane AP Receptor Antagonists

.

Steven E Hall Bristol-Myers Squibb Pharmaceutical Research Institute. Princeton. New Jersey 08540

I . Introduction ............................................................... I1. Compilation of TxA2 Antagonists by Structural Class .......................... A. Specific Antagonists .................................................... 1. Early Analogs ....................................................... 2. PGHzflxA2-Derived Compounds ...................................... 3. PGD2-Related Compounds .............. ........................... 4 . Sulfonamides ........................................................ 5. Heterocycle-Based Analogs ................................. 6. Miscellaneous Nonprostanoi ists ............................. ..................................... B . Mixed-Activity Antagonists . . . . 1. Indoles ................... ................................. 2. Quinones ........................................................... 3. Picotamide .......................................................... 4 KW-4099............................................................ 5. Combined TxA2 Receptor AntagonistlSynthase Inhibitors ................ 6. TxA2 Receptor AntagonisffPG12Mimic ................................. C. Comparison of Structural Classes ........................................ I11. In Vitro Activity of Thromboxane Receptor Antagonists ....................... IV. Receptor Characterization................................................... V . In Vivo Characterization of Thromboxane Receptor Antagonists ................ A. Thrombosis Models ..................................................... B. Ischemia Models ........................................................ 1. Myocardial Infarction ................................................. 2. Stroke .............................................................. C. Pulmonary Disorders ................................................... D. Renal Disorders ...... ........................................... E . Shock ............... ........................................... F. Sudden Death .......................................................... G . Miscellaneous .......................................................... H. TxA2-Dependent Responses of Various Endogenous Mediators ............. VI. Clinical Studies ..................... .................................... A. TxA2 in Human Pathophysiology ........................................ B. Clinical Status of TxA2 Receptor Antagonists .............................. VII . Future Directions ........................................... References ........................................................

.

503 505 505 505 507 510 512 517

519 522 522 522 523 524 524 525 526 528 528 536 537 541 541 547

547 549 549 549

555 557 557 557 560 560 563

I. INTRODUCTION Modulation of either the synthesis or the activity of arachidonic acid (AA) metabolites continues to be an area that attracts substantial research interest. Once considered as only the biosynthetic precursor to the prostaglandins. arachidonic acid is now known to lead to at least three general classes of eicosanoids. prostaglandins. leukotrienes.' and lip ox in^,^ as well as the reMedicinal Research Reviews. Vol . 11. No. 5. 503-579 (1991) CCC 0198-6325lsll050503-77W.00 8 1991 John Wiley & Sons. Inc.

HALL

504

c:, Arachidonic acid (AA)

1

cycloxygenasc

1

peroxidase

receptor activation

Vasospasm Bronchospasm Platelet Aggregation

1, PGHZ

Thromboxane Synthase

HO

-

CH3

OH

3, PGIz

2, T x A ~ Scheme I. Arachidonic acid metabolism.

lated hydroxyeicosanoic acids and epoxyeicosanoic acids. Of the myriad biologically active compounds in these groups, thromboxane A2, TxAz, and prostacyclin, PGIz, are among the most interesting due to their opposing biological activities.- Thromboxane A2 is a potent stimulator of platelet aggregation and induces contraction of both vascular and airways smooth muscle.- In contrast, prostacyclin is a nonspecific inhibitor of platelet aggregation and elicits vasorelaxation. These opposing profiles prompted Moncada and Vane9,10to propose that a delicate balance exists in the biosynthesis of these two eicosanoids and that disruption of that balance in favor of thromboxane Dr. Steven E. Hall received the B.Sc degree in Chemistryfrom Central Michigan University in 1976. After two years of research in furan chemistry with the Chemicals Division of Quaker Oats Co., he resumed his studies at Massachusetts Institute of Technology and received the Ph.D. degree in Organic Chemistry in 1982. Since joining The Squibb Institute for Medical Research in 1982, where he is currently Associate Director, Cardimscular Chemistry, his research has focused on modulation of the arachidonic acid cascade, and in particular, the design and synthesis of cyclooxygenase inhibitors, leukotriene receptor antagonists, and thromboxane A2 receptor antagonists.

THROMBOXANE A2 RECEPTOR ANTAGONISTS

Difluoro-TxAz (4)

I-BOP (6)

505

Rs-61756-007(5)

EP-171 (7)

Scheme 11. TxA2 mimics.

would result in the expression of the thrombogenic and vasospastic activities of TxA,. This dichotomy has generated extensive interest from the pharmaceutical industry, resulting in the synthesis of PGI, mimics, TxA synthase inhibitors (TSI), and TxA,/PGendoperoxide receptor antagonists (TRA). With respect to the latter two approaches, the former has received greater interest due to the hypothesis that inhibition of thromboxane synthesis would also be accompanied by an increase in PGI, production as a result of the increased availability of the precursor, PGH,. It should be noted that this redirection of eicosanoid biosynthesis, from TxA2to PG12, must occur for this approach to be effective, as PGH2 shares the same biological profile as thromboxane A2 and interacts at a common receptor." Inefficient conversion of PGH, to PGI, would result in the accumulation of PGH,, which could elicit a response through activation of the PGH,/TxA2 receptor. In addition, this redirection necessarily involves diffusion of PGH2 from its source of production, i.e., platelets or monocytes,12to the vascular wall since the platelet does not contain PG12 synthase. Experimental studies have shown that this redirection does occur in the laboratory setting; however, there is conflicting evidence for the viability of this process in humans.13-16 These concerns have prompted our laboratory, as well as others, to approach the modulation of thromboxane via the discovery and development of specific TxA2 receptor antagonist^.'^ This review will describe the various structural classes of antagonists, their in vitro and in vivo activity, and clinical status. 11. COMPILATION OF TxAz ANTAGONISTS BY STRUCTURAL CLASS A. Specific Antagonists 1. Early Analogs

The development of structure-activityrelationships (SAR) toward the identification of TxA, receptor antagonists actually began prior to the discovery

HALL

506

13-APA (8)

13-HAPA (9)

Scheme 111.

of TxA, itself, as the UpJohn group had prepared a number of stable endoperoxide (PGH,) mimics. These early analogs, U-46,619 and U-44,069,18continue to be widely used as PGH2/TxA2mimics (the former being six times more potent'' than PGH,). In 1975, Hamberg et al. proposed the chemical structure of rabbit-aorta-contracting substance as thromboxane A,,'' but it was not until nearly 10 years later that the total synthesis of this unstable molecule was achieved.21," In the intervening years, a number of PGH, and TxA, structural analogs were prepared.= In general, these analogs shared the same two side chains present in PGH, and TxA2, but possessed varied ring systems in which one or more of the oxygen atoms of the bicyclic ring were replaced with nitr~gen,",~ carbonrZm2,or The SAR observed with these early analogs established that the 15-hydroxyl group as well as the relative stereochemistry of the two side chains were critical for potent biological activity. Recently, several new PGH,/TxA, mimics have been described,-l including a compound that possesses the oxetane-acetal ring s y ~ t e m ~present '?~ in TxA,. It is interesting to note that agonistic activity is dependent on the stereochemistry at C(15) even in analog 4, which possesses the same ring system as TxA, itself. Whereas 4 is a potent thromboxane mimic, the C(15)alcohol epimer is a TxA, receptor antagonist in the platelet.39No direct comparison between these agonists exists. However, the most potent mimics appear to be the pair of closely related 7-oxabicyclo[2.2.llheptane derivatives, I - B O P and EP-171.38,4*,43 On six isolated smooth muscle preparations, EP171 was 33-167 times more potent than U-46,619 as a spasmogenic agent and was %-fold more potent as a stimulator of platelet aggregation. EP-171 is also a potent TxA, mimic in vivo, causing a slowly developing state of shock in mice ending in death after a l-pg/kg i.p. dose.41 The first TxA2antagonists to be described were a series of 13-azaprostanoic acids.4441 13-APA and its cyclohexane derivative 9 inhibited U-46,619-induced contractions of rat aorta ( K b = 7.1-13.2 pM), U-46,619-induced 5-HT release from platelets (Iso = 3.4-9.1 AA-induced platelet aggregati~n,~~ and reversed the calcium mobilization and shape change induced by AA. This discovery was followed by a number of allylic-alcohol-based antagonists such as pinane-TXA, (10,PTA2),5055carbocyclic-TXA, (11, CTA2)r53and a series of 7-oxabicyclo[2.2.llheptane derivatives.% Many of the subsequent prostanoid-based antagonists have their structural roots in one or more of these early analogs. Differences in platelet and vascular thromboxane receptors were suggested, as PTA2and CTA, were potent con-


507

carbocyclic-TxA2(11; cTA2)

pinane-TxA2(10;PTAd

-

OH

SQ 26,536 (12) Scheme IV.

tractile agents on vascular smooth muscle but inhibited platelet aggregati~n.~~ Whether inhibition of platelet aggregation by PTA, and CTA2was due entirely to TxA, receptor antagonism is not clear since both of these analogs also bind to inhibitory PG receptors on the platelet.% Early work established that replacement of the unstable ring systems of either PGH2 or TxA, with chemically stable bicyclic rings led to analogs that possess partial agonistlpartialantagonist activity. The identification of potent, pure receptor antagonists was a more formidable challenge that was not realized until years later. 2. PGHz/TxAz-Derived Compounds

The transposition of oxygen and carbon atoms in PGH2 led to the 7-oxabicycloheptane class of a n t a g o n i s t ~ . ~ . ~ ~ - ~ l Potent antagonistic activity in the series was only realized if the two side chains were present in the cis-ex0 orientation rather than the trans relationship present in PGH, and TxA,. The bicyclic ring was important for optimal activity, as a series of tetrahydrofurans and tetrahydrothiophenes were 650fold less potent than their oxabicycloheptane counterparts.62Despite their potent antiplatelet activities, many of these allylic alcohols were not completely specifica or displayed partial agonistic activity on smooth muscle (i.e., rat stomach). Unique among these compounds was alcohol SQ 28,668 (13), which was completely free of any direct contractile activity." Although this compound entered clinical trials at Squibb,65its development was superseded by another 7-oxabicycloheptane derivative (vida infra). Subsequent synthetic efforts from these laboratories have focused on identification of suitable replacements for the o-chain allylic alcohol, as the agonistic activity appeared to be closely linked to this group. A series of compounds in which the allylic alcohol was replaced with a thioether (14)@r6' were potent TxA2antagonists in the platelet but, like the allylic alcohols, possessed direct spasmogenic activity in the rat stomach strip. Concurrent with these studies, a number of a. 7-0xabicyclo[2.2.1]heptanes.

HALL

508

9

?

q

C

OH

0

a

H

0

SQ 28.668 (13)

SQ 29,524 (14)

H \ \ 4

SQ 29,548 (15)

SQ 30,741 (16)

SQ 30,457 (17)

SQ 33,552 (18)

Scheme V.

oxabicycloheptanes were prepared in which the allylic alcohol was replaced with an amine,68amide,68 or other nitrogen-containing functional Although these uzu-analogs were initially less potent than the allylic alcohols, semicarbazide SQ 29,548 (15) was soon identified as a potent and highly specific antagonist.70 This compound was one of the first 14um-7-oxabicycloheptanes to be prepared and has been extensively characterized (for a compilation of in vitro and in vivo data, see Ref. 60).The possibility of toxic side effects precluded its development as a potential therapeutic agent; however, it has become an important research tool in the thromboxane field and is commercially available as the tritiated analog.71Unique to the 14um class of antagonists was the observation that these analogs, unlike the allylic alcohol SQ 26,53656,59 and its congeners, were uniformly free of agonistic activity with only one exception. Sulfonamide 17, isosteric with the allylic alcohol functionality, actually stimulated platelet aggregation at high concentrations. SQ 30,741 (16)emerged from the SAR studies within the 14-uza series as a potent and selective compound. This antagonist is currently entering Phase I1 clinical trials. A summary of the SAR within the 14-am series is illustrated in Scheme VI. The nitrogen atom at position 14 was a prerequisite to potent antagonistic activity, which was only maximized with the incorporation of an additional nonbasic nitrogen (i.e., amide, carbamate) at position 17. Despite the rigid requirements for the position of the nitrogen atoms, the lipophilic tail could be altered extensively with little effect on activity. Recent studies have identified the related semicarbazone SQ 33,552 (18), which possesses the 4-Z-


509

B

sa 29,548

I lo

I

30,741

30,339 30,620

qoJ

increasing activity

CSHW

\

non-basic nitrogen (amide) at position 17 basic or non-basic nitrogen at position 14 is critical for high receptor affinity

Scheme VI. Common structural elements of potent 14-Aza-7-Oxabicyclo[2.2.l]heptaneTxA2antagonists.

hexenoic acid a-chain in place of the natural 5-Z-heptenoic acid moiety. This modification has been demonstrated to result in an increased duration of action due to the reduced susceptibility of the a-chain toward @-oxidation. As described in Section V.F, SQ 33,552 exhibits an exceptional duration of action in viva" that exceeds that displayed by all of the TxA2 receptor antagonists currently under clinical development. b, Pinanes. The t3.1.11 skeleton of pinane duplicates the shape of the dioxa[3.1.1.]heptane nucleus present in thromboxane A2. Researchers at Ono used the pinane framework in the construction of potential antagonist^.^^ In analogy to the Squibb work, replacement of the natural w-chain with an amine or amide-containing side chain led to antagonists such as Ono-11120 (19).In contrast to the SAR developed in the oxabicycloheptanes, the optimal position for the w-chain nitrogen is at the 13-position (directly attached to the bicyclic framework). Optimization of their initial lead provided Ono-3708 (20),7p76 which possesses a profile similar to that of SQ 30,741, and is currently in Phase I1 clinical trials for subarachnoid hemorrhage and angioplasty. The aminopinane skeleton was also used by Halushka et al. in the preparation of a radioligand via iodination of the appropriate phenol (21).” A series of differentially substituted aryl analogs were evaluated in platelets and saphenous veins, which led Halushka and Mais to propose that different receptors exist. The related ether (22), prepared by Freid et al., also possessed TxA2antagonistic activity.78 c. Norbornanes. The bicyclo[2.2.l]heptane framework has also been in-

HALL

510

0110-3708 (20)

Ono-11120 (19)

bLF-co2H 21 OH

Scheme VII. Pinane-based antagonists.

corporated into TxA2antagonists.79 Replacement of the natural o-chain with the phenoxy-substituted allylic alcohol results in a potent agonist (23)that elicits irreversible aggregation." In contrast, incorporation of a semicarbazone functionality as in EP-045 (24)81,82 results in a compound that expresses TxA2receptor antagonistic activity. Unlike allylic alcohol 23, EP-045 did not display direct contractile activity which has been in smooth muscle tissue.83A related derivative, EP-092 (E), described as more potent than EP-045,s91 was under development by Searle but apparently further work with this antagonist has been s~spended.~'. The structure of additional PGH2/TxA2analogs that have been patented but for which there is no data are included in Scheme VIII. 3. PGD2-Related Compounds

Although PGD2and PGH2/TxA2act at distinct receptors on the blood platelet, PGDz is a potent bronchoconstrictor, and this activity has been demonstrhted to be the consequence of TxA2/PGH2receptor activati~n.~',~~ PGD2induced pulmonary vasoconstriction in sheep was dependent, in part, on activation of the TxA2 receptor.93Cross-reactivity at platelet TxA, receptors was also shown in some species as PGD2 bound to TxA2 receptors in guinea pig platelet^.^^ AH 19,437, the first Glaxo TxA2 antagonist to be described in detail,9598emerged from their SAR studies on 13azaprostanoicacids? Briefly, sulfonamide 31 was an initial lead that possessed both agonistic and antagonistic activity. Oxidation of the C(11)-hydroxyl group led to a compound that purportedly was free of agonistic effects. This compound antagonized PGF2,-induced contractions of guinea pig lung strips but had no effect on epinephrine-induced platelet aggregation (TxA2dependent). Replacement of the sulfonamide-o-chain with basic amine-containing groups afforded compounds that possessed both antiplatelet and antivasospastic activity. In this series of compounds, exemplified by AH 19,437 (32), the benzyloxy group at C(9) was critical for potent antagonistic activity as had been observed with


511

*90 min (R)] Increased incidence of lysis (2/14 to 14/16), which was not duplicated by ASA 5 mgkg (4/11\ , --,

prevented reocclusion and reduced the timetoreflow(56 f 7min-+11 f 2min) enhanced the extent of reflow 174%

reduced time to lysis from 66.8 f 8.6 min to 25.4 f 5.2 min reduced time to reflow from 32 f 5 min to 21 2 7 min and reduced the inadence of reocclusion (83%+ 50%) reduced time to reflow (32 2 5 min + 11 2 2 min) and reduced incidence of reocclusion (83%+ 11%) completely blocked reocclusion and cyclical flow reductions

abolished cyclical blood flow reduction increased the number of successful reflows

prevented reocclusion and enhanced reflow

Results

317

316

318

315

314

313

313

312

319 312

311

Ref.

r r

s

0


541

Limited studies suggest that TxAz also plays a role in venous thrombosis; administration of SQ 30,741 reduced the dose of heparin required to prevent venous t h r o m b o ~ i s . ~ , ~ ~ ~ Despite the improvement in available thrombolytic agents such as tPA, thrombotic reocclusion of the affected vessel remains an important clinical problem. A number of antiplatelet agents have been evaluated for their ability to inhibit the reocclusion phenomenon in the laboratory setting. Thromboxane receptor antagonists of varying structure have been shown to not only reduce SQ 29,548,314 Rthe incidence of reocclusion (SQ 30,741,311BM 13.177,31z,313 68,070315)but also in some cases to decrease the time to lysis (BM 13.177,3w or R-68,070,315,316) increase the incidence of successful lysis (BM 13.177j1z,317) increase postreperfusion flow (SQ 30.7413119318).The latter activity supports the hypothesis that an important limitation to flow restoration is TxAz-mediated vasoconstriction. It was noted that the increased incidence of successful lysis associated with BM 13.177 treatmenel’ was not duplicated by aspirin (ASA). In a related study, GR 32,191 abolished the cyclical flow reductions following tPA-induced thrombolysis, which persisted after treatment with the thrombin inhibitor a r g ~ t r o b a n Other . ~ ~ ~ antiplatelet agents have demonstrated beneficial effects following thrombolysis; however, when administered at the minimal doses required to inhibit cyclical flow reductions in the dog, Willerson et al. observed that SQ 28,668 or SQ 29,548 were more effective than a 5-HTz receptor antagonist in inhibiting platelet deposition at the stenosis site.3z0This same group found that nitroglycerin and diltiazem failed to m o w the frequency or severity of cyclical flow reductions.321Epinephrineinduced cyclic flow reductions in severly narrowed canine coronary arteries were also effectively blocked by the TxAz antagonist SQ 29,548 and a 5-HTz receptor a n t a g o n i ~ tThis . ~ ~combination of pharmacological agents was shown to be more effective than either agent alone in preventing reocclusion following tPA-induced t h r o m b ~ l y s i s . ~ ~ Combination of iloprost (a stable PGIz mimic) with SQ 29,548 or BM 13.177 ~ ’ ~combination of BM resulted in a synergistic antiplatelet effect in ~ i t r o . The 13.177 with a TSI (diazoxiben)also exhibited synergistic effects in blocking collagen-induced platelet aggregation in whole blood.325This synergism was demonstrated in vivo; combination of BM 13.177 with iloprost was effective in reducing thrombosis in the rat at doses in which either agent alone was ineffective,3z6BM 13.177/ketanserintreatment resulted in a prolonged bleeding time in the rat,3z7and AA-2414/CV-4151(TSI), at doses which singularly had no effect(0.1 mglkg, P.o.), sigruficantlyinhibited thrombus formation in the rabbit carotid artery.3z8In an indirect measure of in vivo platelet activation, S-145 (10 mglkg, p.0.) antagonized the ECG changes associated with intravenous injection of collagen in rats and mice for more than 4 h.3z9In this model, S-145 was 4-13-fold more potent than Ono-3708, dazoxiben (a TSI), and ASA.

B. Ischemia Models 1. Myocardial Infarction

A pathophysiological role for TxAz in ischemic injury has been documentedm; elevated TxBz (stable metabolite) levels in the circulation

542

HALL

draining the ischemic region have been observed, stable TXA, mimics cause or enhance ischemic injury,=’ and specific receptor antagonists ameliorate these effects. As summarized in Table VIII, thromboxane receptor antagonists are effective in inhibiting the sequelea in three models of myocardial ischemia: long-term occlusion (4-5 h), moderate occlusion time (90 min) followed by reperfusion (4-5 h), and brief occlusion (15 min) followed by reperfusion (cardiac stunning phenomenon). The beneficial effects of these compounds include reduction in infarct size, reduction in neutrophil accumulation, increased subendocardial blood flow, presenration of myocardial CK activity, increased survival rates, and inhibition of ischemia-induced arrythmias. Noteworthy in these studies is the fact that the beneficial effects of these compounds are maintained even when the antagonist is administered immediately prior to reperfusion. For example, SQ 29,548 (0.2 mg/kg + 0.2 mg/kg/h, i.v.) inhibited the decline in segmental shortening that occurred following a 15-min occlusion of the left anterior decending (LAD) coronary artery in the dog, regardless of whether the antagonist was administered 15 min prior to the occlusion or 1 min prior to reperfusion.332 SQ 29,548 (0.2 mg/kg + 0.2 mg/kg/h, i.v.), given 2 min prior to reperfusion [90 min left circumflex (LCX) coronary artery occlusion/5-h reperfusion] reduced infarct size and increased subendocardial blood flow in the dog.= Likewise, SQ 30,741 (2.1 mg/kg + 0.5 mg/kg/h, i.v.), given 2 min prior to reperfusion [90 min left circumflex (LCX)coronary artery occlusion/5-h reperfusion] resulted in a 36% reduction in infarct size in monkeys.318In a occlusion (90midreperfusion) (3 h) dog model, SQ 30,741 treatment (1mgkg + 1 mgkg/h, i.v.) resulted in a near doubling of subendocardial blood flow. Oxygen extraction was similar in control and treated groups, although the O2 consumption increased in the SQ 30,741-treated group suggestive of myocardial preservation.334 Thromboxane receptor antagonists have also been effective in inhibiting the myocardial effects of other inflammatory stimuli. SQ 29,548 partially inhibited the coronary vasoconstrictive effectsof neuropeptide Y in dogsm and, along with BM 13.505, inhibited both the coronary vasoconstriction and contractile dysfunction induced by complement (&.% In a model of exercise-induced myocardial ischemia in dogs, BM 13.177 (10 mg/kg, i.v.) did not improve regional function or blood flow in poststenotic ischemic subend~cardium.~’ In contrast, SQ 29,548 decreased ST segment elevation and increased blood flow to the ischemic region in a model of pacing-induced i s ~ h e m i a . Following ~ , ~ ~ ~ balloon catheter injury to the lower aorta in the rabbit, vasospasm of the collateral arteries was observed which could be partially blocked by either SQ 29,548 or a 5-HT2 antagonist. Combination of these two treatments resulted in complete suppression of vasospasm.M o TxA2 receptor antagonists have demonstrated beneficial effects in other models of ischemic insult. Pretreatment with SQ 29,548 prevented the ischemia-induced increase in neutrophil hydrogen peroxide production following bilateral hindlimb ischemia in ratsM1 and inhibited the ischemia/ reperfusion-induced pulmonary hypertension in the isolated perfused rabbit lung.= In contrast to the beneficial effect of TxA2 receptor antagonists, TSIs have

0.03 mg/kg/min

0.2 mgkg + 0.2 mgkgh i.v.

4 mgkg i.v.

SQ 29,548

SQ 29,548

0.2 mgkg + 0.2 mgkg/h i.v.

2.2 mgkg + 2.2 mg/kg/h i.v.

Dose

SQ 29,548

SQ 29,548

SQ 29,548

SQ 29,548

Antagonist

30 min prior to ischemia

variable

3 min prior to CSa

rat

dog

Pig

dog

sheep

preinjury

15-min preocclusion or 1min prior to reperfusion

rat

Species

preinjury

Timing of dose

pacing (LAD & stenosis) induced ischemia 48-h occlusion

Administration of Cs. (500 ng, i.c.)

reperfusion 15-min occlusion of LAD; 5-h reperfusion

2-h hind limb ischemia; 30-min

4-h hind limb ischemia; 60-min reperfusion

Model

Table VIII TxAz Antagonists in Ischemia/ReperfusionInjury

*

Inhibited ischemia-induced increase in neutrophil H 2 0 2 production; inhibited the ischemia-induced enhancement of the response to Ph4A Inhibited the increase in permeability and leucocyte sequestration Both dosing regimens afforded protection in that segmental shortening had returned to 60% of base line values vs. 20% for control animals Blocked Cs,-induced decrease in coronary blood flow and segmental shortening Reduced S-Televation by 45% at 70 min after dosing; increased blood flow (40%) to ischemia region Reduction in infarct size (44 3 --* 32 -C 4); preserved LV CK level (1.8 --+ 3.11 IU/mg protein)

Result

(continued)

551

338 339

549 550

332

518

547

Ref.

x! w

v,

cl

$

>

!8

E Q3

N

>

m

!

3 ??z

13-APA

SQ 30,741

SQ 30,741

SQ 29,548

SQ 30,741

SQ 30,741

SQ 29,548

SQ 29,548

Antagonist

15 min preocdusion

3omin postocclusion

1.5 mgkg + 1.5 rn@g/h i.v.

2 min prior to reperfusion

2.1 mgikg + 0.5 rn&g/h i.v.

5mgikg + 5 mg/kg/h i.v.

15 min postocclusion


A. 1Omin postocclusion or B. 2 min prior to reperfusion

2mgikg + 2 mgikgih i.v.

1 mgikg + 1 rngikgh i.v.

1 mgkg 1 mgikgih i.v.

+

0.2 mgikg 0.2 mgikgih i.v.


2 min prior to reperfusion

0.2 mgikg + 0.2 mgikg/h

+

Timing of dose

Dose Species

Model

5 h ligation of left coronary

90-min L c x occlusion; 5 h reperfusion 15-min LAD occlusion; 5 h reperfusion

90-min L c x occlusion; 22.5 h reperfusion 6-h ligation of coronary

90-min L c x occlusion; 5 h reperfusion 90-min L c x occlusion; 5 h reperfusion

90-min LCX occlusion; 5 h reperfusion

Table VIII Continued

No effect on collateral or reperfusion flow but improved segmental shortening at all times; at 5 h, improved from 3 f 16% to 44 f 10% of baseline values Inhibited ST elevation 3-5 h); did not inhibit CK activity loss

Reduced loss of CK activity; improved survival rate (58% + 100%) 36% reduction in infarct size

Post reperfusion subendocardial flow increased (71 & 1 6 - +109 2 15 mUmin/100g) Reduction in infarct size (60 f 5 to 25 f 3%)

B)

30% reduction in infarct size (Dose

A)

50% reduction in infarct size (Dose

Reduction in infarct size (57 2 7 to 34 f 8%) and increased subendocardid BF (54 f 10 to 93 % 14 mUmin/100 g) Reduction in infarct size (79 f 2 to 45 f 8%)

Result

557

556

318

555

553

553 554

552

333

Ref.

r

5r

E

5 mgkglh i.v.

20 mgikgh i.v.

BM 13.505

5 mgkg + 0.15 mglkglmin i.v.

BM 13.177

BM 13.177

2 mgikg + 2 mgkg/h i.v.

30min postocclusion

postocclusion

3omin

preocclusion

30min predigoxin 40-min LAD occlusion

5-h coronary occlusion 3-h LAD occlusion, 2-h reperfusion

cat

cat

digoxin-induced anythmias

dog

guinea pig

4O-min LAD occlusion

dog

0.3 mgikg i.v.

L-655,240

ICI 185,282

3 grades of partial coronary occlusion

dog

1 min postflow reduction

0.1 mgikg i.v.

AH 23,848

20 min preocclusion

5-h ligation of left coronary

cat

30 min postligation

2mgkg + 2 mgkg/h i.v.

SQ29,W

2,800)

--f

(continued)

50% inhibition of ST segment elevation; inhibited loss of myocardial CK activity Coronary dilatory effects observed only in the presence of flow restriction Survival increased (10% 70%); selective inhibitor of early (phase la) arrythmias Survival increased (35% -+ 100%); increased time to first arrythrma; decreased VF (53% + 0%) During ischemia, reduced incidence of VT (86- 22%) and VF (30+ 10%);postreperfusion VF also reduced (86%-+ 44%); survival increased (10% 50%) Reduction in ST elevation from 3 to 5 h (30%);no effect on platelet count; reduced CK loss (41% + 20%) Reduction in ST elevation, largely prevented Q-wave development; inhibited increase in white cell count (26,700 2 2,100+ 13,700 2

1 mgkg i.v.

BM 13.505

pretreatment

10 mgkg i.v.

Ono-3708 L-655,240

2.2 mgkg + 2.2 mglkgih

15 min preocclusion

1 mgkg i.v.

AH 23,848

SQ 29,548

lmin preocclusion 3omin preocclusion

30 mglkg i.p.


5min preocclusion

lmin preocclusion

Timing of dose

BM 13.505

1 mgkg + 10 mgkgh i.v.

5 mgkg i.v.

BM 13.505

Bay U 3405

30 mgkg i.p.

Dose

BM 13.505

Antagonist

rat

rat

rat

dog

rat

30-min coronary occlusion; 4 h reperfusion

rat

~~

~

90-min occlusion of liver circulation 4 h bilateral hindlimb tourniquet ischemia

6-h occlusion of LAD; 30-min reperfusion Bmin occlusion, 24-h reperfusion 40-min LAD occlusion, reperfusion 10-min LAD occlusion; 10-min reperfusion

30-min occlusion; 5.5 h reperfusion

Model

rat

Species

Table VIII Continued

Preserved myocardial CK levels and inhibited PMN infiltration 50% reduction in ischemia-induced extrasystoles and VF also reduced (88% -3 25%) Did not affect reperfusion anythrmas and actually increased the duration of VF during the occlusion Achieved a nonsigdicant increase in survival (17%+ 50%) Prevented ischemia-induced increase in neutrophil H 2 0 2 production and enhanced responsiveness to PMA stimulation

50% reduction in infarct (39 f 6 + 19 f 7%);inhibited loss of CK and reduced MPO levels in LV free wall Abolished the infarct size enhancement caused by 3%cholesterol diet (3 days), 75 ? 8 + 43 f 11%;BM had no effect on infarct size in rabbits fed normal chow Reduced infarct expansion by 65%

Result

341

573

572

571

570

569

568

566 567

Ref.


547

not been uniformly effective in ischemidreperfusion models. For example, DP-1904 failed to decrease infarct size in rabbits resulting from a 30-min coronary occlusion followed by 72 h of reperfusion.343 2. Stroke

The capability of brain tissue to synthesize TxA, was suggested by the ability of locally applied t-butyl hydroperoxide to induce local vasoconstriction, which was antagonized by SQ 29,548.% That the pial vessels themselves were the source of the TxA2 was supported by the fact that no platelet aggregation was observed and that the dwell time of platelets at the site was less than one second.345Ono-3708 inhibited the contraction induced by STA, in a competitive fashion with pA2 value of 8.7.% Ono-3708 also inhibited, in a noncompetitive manner, the contractions induced by PGF, (neither STAz or the antagonist had any effects on membrane potential or excitatory junction potential). In a model of subarachnoid hemorrhage, Ono-3708 prevented the cerebral vasospasm associated with injection of b l ~ o d . ~Other , ~ ’ effects of thromboxane antagonists in the cerebral circulation are summarized in Table IX.

C. Pulmonary Disorders A number of noxious agents have been demonstrated to elicit pulmonary vasoconstriction and bronchoconstrictionm via the synthesis and actions of thromboxane AZ,which itself may be partially responsible for the development of airway hyperresponsivenes~.~~ Stable TxAz analogs such as STAz have been shown to cause vasoconstriction; in the isolated perfused lamb lung, STAz caused an increase in pulmonary artery pressure which was inhibited by Ono-370tLrn The pulmonary edema caused by STA, was also antagonized by Ono-3708 but, interestingly, was increased by administration of PGIz. In the guinea pig, histamine injection into the pulmonary circulation caused an increase in perfusion pressure that was dependent on TxAz as SQ 29,548 blocked this response.35’In isolated rabbit lungs, complement-induced increase in pulmonary vasoconstriction was also shown to be dependent on SKF 88,046 antagonized the contraction of guinea pig lung parenchyma strips to LTD4, PGF,,, PGDz, and carbocyclic TxAz.353Apparently, in the guinea pig interaction of LTD4 with its receptor results in synthesis of TxA,, which mediates a portion of the contractile response. The other agents (PGD,, PGF,,) are believed to interact directly with the airways TxAz receptor. In addition to their effects on airways smooth muscle, stable TxA, mimics (U46,619 and CTA,) increased tracheal mucous gel layer thickness in the rat, an effect that was attenuated by the antagonist PTAz.354 Inhaled PGD, causes profound bronchoconstriction in the guinea pig, which is mediated via the TxA, receptor since the response was abolished by a TxA2 antagonist BM 13.177 (2.5 mg/kg, i.v.) but not by the PGDzreceptorantagonist BW A868~.%~ Other TxAzreceptor antagonists have also shown similar activity in inhibiting the bronchoconstrictive effects of PGDz. Airways hyperreactivity which results from O3exposure appears to be TxAz-dependent;U-46,619, like O ,, enhanced field-stimulated contractions of canine trachea. This enhancement was blocked by SQ 29,548.356

GR 32,191

0.1 mg/kg/min

30 min prior to insult

cat

rabbit

0110-3708

0110-3708

rat

cat

dog

AH 23,848

0.1 mg/kg/min i.v.

0110-3708

2-72 h following injection of blood 1 h postinfusion of STAz

Species

cat

0.01 mg/kg/min i.v.

Ono-3708

Timing of dose

AH 23,848

Dose

Antagonist

STAz-induced vasoconstriction U-46,619-induced pial artery contraction U-46,619-induced pial artery contraction experimental subarachnoid hemorrhage bloodCSF-induced contraction of basilar artery electric field simulation of basilar artery

experimental subarachnoid hemorrhage

Model

Result

Did not inhibit cerebral vasospasm but did inhibit the decrease in regional cerebral blood flow GR 32,191 (1-10 nM)abolished neurogenically mediated contractions

Prevented platelet-induced contraction of basilar artery

Prevented vasoconstriction in induced by U-46,619, PGF*,, and norepinephrine

Inhibited STAz-induced basilar artery constriction Prevented vasoconstrction induced by U-46,619 and norepinephrine

Prevented cerebral vasospasm

Table I X TxA2 Antagonists in Cerebral Pathophysiology

577

576

575

574

574

346

347

346

Ref.


549

The pulmonary hypertension following protamine reversal of heparin anticoagulation in sheep was associated with a 20-fold increase in TxB2release. The cyclooxygenase inhibitor indomethacin blocked both the increase in TxB2 levels and the pulmonary hyperten~ion.~’ That the protective effect of indomethacin was due to inhibition of PGH2and TXA, synthesis was provided by Schumacher et al.; SQ 30,741 completely inhibited the pulmonary hypertension following protamine reversal of heparin anticoagulation in sheep,= and pigs.359Other effects of thromboxane antagonists in the pulmonary system are summarized in Table X. D. Renal Disorders Increased renal thromboxane production has been proposed to be a key element in the pathogenesis of a number of renal diseases [Refs. 360362, 363(review)]such as total nephrectomy, hydronephrosis, transplant rejection, and diabetes. The results summarized in Table XI outline the effectiveness of thromboxane receptor antagonistsin models of these disease states. A number of these studies have focused on the renal toxicity of cyclosporine treatment, which appears to be mediated, at least in part, by TXA,. GR 32,191 was demonstrated in several different models to increase glomemlar filtration rate (GFR)and renal blood flow (RBF) in experimental transplants.Recent evidence suggests that TxA, may also have direct effects on the development of glomemlosclerosis and interstitial fibrosis. Klotrnan et al. found that GR 32,191 inhibited the dose-dependent increases in laminin A, B1, and B2 chains caused by incubation of teratocarcinoma cells with U-46,619.367 The renal vasoconstriction associated with hypercholesterolemia in rats was demonstrated to be mediated by TxA2 as BM 13.505 reversed the vasoconstriction and the decrease in single nephron blood flow and GFR caused by U-46,619.= Treatment of rats with SQ 29,548 (8mg/kg)or L-641,953(50 mg/kg) stimulated plasma renin activity.%’ This effect was dependent on PG and TxA, synthesis as indomethacin (cyclooxygenase inhibitor) prevented the stimulatory effect.

E. Shock The ability of TxA2receptor antagonists to ameliorate the pathophysiology of septic shock has been suggested by studies in rats, sheep, rabbits, pigs, and guinea pigs in which these agents blocked the increase in pulmonary vascular resistance, increased survival, attenuated thrombocytopenia, and inhibited increases in hematocrit (Table XI). The level of protection was not uniform across the models; 0.75 mg/kg (i.v.) SQ 29,548 abolished the lethal outcome of endotoxin infusion in the pig3’* whereas 30 mg/kg (iv.) BM 13.505 had no effect on lethality in the rat.371

F. Sudden Death Myers et al. were the first to show that injection of a TXA2 mimic into mice resulted in lethaliVR that was blocked by the antagonist SQ 26,536, sup-

1 mgkg i.v.

0.75 mgkg i.v.

SQ 29,548

0.2 mgkg + 0.2 mgk&min i.v. 3 mgkg i.d.

AH 23,848

L-641,953

SQ 29,548

2.2 mgkg + 2.2 mgkg/h i.v.

1.5 mgkg i.v.

SQ 29,548

SQ 29,548

5 mgkg i.v.

Dose

SQ 29,548

Antagonist

piglets

dog

conscious sheep dog

sheep

rabbit

cat

Species

ACh-induced pulmonary hypertension Limb ischemia induced pulmonary edema & hypertension Adenosine induced pulmonary vasoconstriction U-44069induced bronchoconstriction Ascaris-induced bronchoconstriction Group B streptococcus induced pulmonary hypertension

U-46,619-induced bronchoconstriction

Model

Result

B

3h

Marked inhibition of bronchoconstriction, no effect of TSI (U-63,557A) Pretreatment inhibited pulmonary response which was also reversed with posttreatment with SQ 29,548

Significant inhibition for

Nearly complete blockade of bronchoconstriction for 1 to 2 h; did not block bronchoconstriction due to PGFz, or PGDz Abolished pulmonary responses but did not affect ACh-induced systemic hypertension Prevented increase in mean pulmonary artery pressure, lung permeability, and leukosequestration Response abolished

Table X TxAz Antagonists in the Pulmonarv System

584

583

582

581

580

579

578

Ref.

r r

BM 13.177

S-145

Bay U 3405

L-670,596

SQ 30,741

SQ 29,548

25 mgkg + 0.75 mgkg/min i.v.

0.032 mgkg p.0.

1 mgkg + 0.025 mgkdmin i.v. 30 min prior through 8 h after challenge 0.014.1 mgkg i.v. 0.1-1.0 mgkg p.0.

10 mgkg i.v.

ARDS model-endotoxin administration to sheep with chronic lung lymph fistulas

U-44,069-induced bronchoconstriction

guinea pig

sheep

Antigen-induced bronchoconstriction

Agonist-induced increase in pulmonary artery pressure (PAP) Heparin-protamine induced pulmonary hypertension Antigen-induced early and late responses

guinea pig

allergic sheep

sheep

piglets

70% maximal inhibition of bronchospastic response; ED% = 0.05 mgkg i.v. (0.57 mgkg P.0.) Near maximal inhibition maintained for 6 h, which exceeded that observed with 3.2 mgkg, p.0. S Q 29,548 Attenuated early increase in pulmonary artery pressure but did not inhibit lymph flows during the later phase; BM 13.177 caused direct increases in pulmonary artery pressure, arterial pressure, and central venous pressure

No effect on the early response but partially inhibited late increase in lung resistance (40 ? 11%);LTD4 antagonist was more effective

Completely abolished pulmonary hypertension

Abolished increased PAP in response to U46,619 & PAF but not hypoxia

126

588

587

586

358

585

0.01-0.1 mgkg/

GR 32,191

rat

14 d following simulated transplant

1 hr prior to volume expansion

0.01 mg/kg/min i.a.

2 mgkg i.v.

GR 32,191

L-670,596

rat

rat

10 mgkg i.v.

rat

BM 13.177

min

rat

3 mgkg p.0. b.i.d.

GR 32,191

Daily starting one day before transplant 30 min infusion

rat

0.01 mg/kg/min i.a.

GR 32,191

Species

Pig

rat rat

0.02-1.0 mgkg i.v.

4-h prediuretic 3045 min prediuretic 5 min prior to agonist administration

L-655,240

S.C.

5 mgkg 50 mi&

rat

SQ 29,548 L-640,035

Dose schedule

8 mgkg i.v. 50 mgkg i.v.

Dose

SQ 29,548 L-641,953

Antagonist

renal denervation; cross-clamping of renal artery; CyA treatment volume expansion in hydronephrotic rats

CyA treatment

two-kidney, one-clip Goldblatt hypertension

renal isograft

TxAz- or U-44,069induced renal vasospasm CyclosporinA (CyA) treatment

furosemide diuresis furosemide diuresis

Model

Result

590 590

589

Ref.

Inhibited the increased tubuloglomerular feedback sensitivity

595

591 Inhibited reduction in renal blood flow (RBF) induced by TxA2, EDso = 0.06 mg/kg i.v. Increased glomerular filtration rate 345 (GFR) and renal blood flow (RBF) and decreased renal vascular resistance Attenuated decline in renal 366 function as assessed by creatinine 592 clearance Significant increase in contralateral 593 kidney inulin clearance and decreased mean arterial blood pressure Tendency toward improved kidney 594 function that was not statistically significant 364 34% increase in glomerular filtration rate and 18% increase in renal blood flow

Inhibited tubuloglomerular feedback (TGF) response by 50% as well as the decrease in single nephron glomerular filtration rate Increased diuretic effect ( + 35%) Increased diuretic effect (+ 62%)

Table XI TxA2 Antagonists in Renal Pathophysiology

r

5r

E

3 mgkg i.v.

mg/kg/h

1

SQ 29,548

SQ 29,548 L-641,953

8mgkg kdh i.v.

+ 8mg/

8 mgkg i.v. 50 mgkg i.v.

BM 13.505 1.5 or 15 mg/kg/d (SKF % , l a ) i.v.

GR 32,191

SQ 29,548

SQ 29,548

+

3 mgkg P.o., b.i.d. 30 mgkg i.p.

GR 32,191

1 mgkg i.v.

2 pgkg/min i.v.

SQ 29,548

BM 13.177

3-30 mgkg p.0.

BM 13.505

6d

7d

30d

daily

Partially prevented deaease in renal plasma flow and GFR High but not low dose improved renal function (increased inulin clearance) Both antagonists increased plasma renin activity; increased PRA was inhibited by a CO inhibitor Partial blockade of the TGF response

rat renal allograft

rat

rat

rat

Amphotericin-Binduced renal vasoconstriction CyA treatment

unilateral right hydronephrosis

CyA treatment in isografted rats CyA treatment

rat

rat

rat

rat

Delayed manifestation of proteinuria and mortality SQ did not effect renal hernodynamics (i.e. reduced RBF and GFR) but caused a sigruficant reduction in blood pressure Attenuated increase in serum creatinine Normalized blood pressure and RBF and partially normalized GFR Reduction in GFR was blocked by SQ and an angiotensin II antagonist AmB-induced decrease in RBF and GFR were abolished

immune complex NZBxW glomedonephritis mice DOCA-salt hypertensive rat

604

364

603

602

601

600

599

598

597

596

1 mgikg i.v.

10 mgikg i.v. over 10 min 5 mgikg i.v.

BM 13.177

13-APT

Ono-3708

KW-3625

2mgikg + 2 mgikgh i.v. 10 mgikg i.v.

30 mgikg i.p.

BM 13.505

EP-092

2 mgikg + 0.1 mg/kg/min i.v. 30 mgikg i.v.

BM 13.177

10 min post-trauma

15 min prior to challenge immediately prior to endotoxin 2 min postendotoxin infusion 5 min prior to endotoxin 30 min prior to endotoxin

5 min prior to C,

rat

rat

rat

rat

sheep

rabbits

Pig

guinea pig

Pig rat

SQ 29,548

5 min prereperfusion

Pig

15 min prior to 60 min post

0.01 m@g/ min 0.1 mg/kg/min 0.5 mgkg i.v.

SQ 29,548

SQ 28,668 s-145

sheep

Species

l h preadministration

Dose schedule

2.2 mgikg t 2.2 mgikgh i.v.

Dose

SQ 29,548

Antagonist

Noble-Collip drum trauma endotoxin infusion

endotoxin infusion

endotoxin infusion

endotoxin infusion

endotoxin infusion splanchnic artery ocdusion and reperfusion C d C , des-Arginduced increase in blood pressure E. wli-induced septic shock endotoxin infusion

Increased survival rate at 24 h (72% vs. 38%)and 48 h (61% vs. 27%)

Inhibited the acute pulmonary vascular response Attentuated thrombocytopenia; did not improve survival (31%) Attenuated thrombocytopenia (85% reduction + 50% reduction in platelet number) Prolonged survival time from 1.9 to 3.3 h

Attenuated early pulmonary vasoconstriction Increased survival (47 + 92%)

Inhibited increase in pulmonary artery pressure, pulmonary vascular resistance (PVR), lung lymph flow, lymph protein clearance Abolished acute increase in PVR survival increased (43 + 100%) Attentuated increase in PVR Attenuated increases in hematocrit and plasma amino nitrogen concentration. Improved survival (14 + 100%) Inhibited the pressor response

endotoxin infusion

endotoxin infusion

Result

Model

Table XI1 TxA2 Antagonists in Shocklike Syndromes

613

612

611

371

610

609

608

607

606

370

370

605

Ref.

s


555

-

GR32.191

+ sQ30.741 BM13505

+ SQ29.548 sQ 32352crs)

--c- ra192,605

0

2

4

6

81012141618202224

Hours After 10 mg/kg Oral Dose Figure 1. Inhibition of U-46,619-induced lethality in the conscious mouse.

porting their hypothesis that TxA2 was the lethal mediator in AA-induced sudden death that had been described by Silver et al.3n Since that time, a number of antagonists have been evaluated in this model; SQ 29,548 in the and rabbitI3" and BM 13.177 mouse374and rabbit,375BM 13.505 in the in the rat.376Lefer demonstrated that sudden death was associated with a 68% decrease in platelet count and a marked release of ATP.378All of these compounds have been evaluated in our own laboratory and allow for their direct comparison. Shown in Fig. 1is the time course for protection following oral doses of the antagonists. Despite the weak antagonistic activity of BM 13.177, this compound was nearly as effective as SQ 29.548. Given the superior profile of BM 13.505 over SQ 30,741, it is assumed that the rapid metabolism of SQ 30,741 in vivo limits its duration of action. A direct comparison of the more potent TxA2 receptor antagonists is shown in Fig. 2; because of the increased potencies in this group of compounds, all were administered orally at 0.2 mg/kg. SQ 33,552, which was a potent inhibitor of U-46,619-induced contraction of rat aorta (PA,= lO.l), afforded superior protection at this dose, providing complete inhibition for more than 10 h.n G . Miscellaneous

Thromboxane A2 receptor antagonists have demonstrated variable effects in models of hypertension.379In saline-drinking rats, the increase in blood pressure induced by infusion of angiotensin I1 was significantly attenuated by SQ 29,548 (4.2 mg/kg, S . C . ) . ~ ' Another TxA, receptor antagonist, AH 23,848 (2 mg/kg, P.o., b.i.d.), also reduced blood pressure in Lyons hypertensive rats.31 A potential role for TxA2in inflammatorybowel disease was suggested by studies in rats where the release of TxB, continued to increase during the

HALL

556

*

10 -

20

0

l

~

l

~

1

-

BM13505 GR32.191 SQ33552 l

-

l

'

l

-

l

-

l

Hours after 0.2 mgkg Oral Dose Figure 2. Inhibition of U-46,69-induced lethality in the conscious mouse.

stage of chronic inflammation despite unchanged levels of the other eicosanoids. In this model, the combined TSI/TxA, receptor antagonist ridogrel (R68,070) reduced the development of chronic inflammatory lesions in the colon.382 A potential role for TxA2 receptor antagonists in preventing development of atherosclerosis was suggested in a study by Lefer et. a1.= BM 13.505 inhibited deposition of cholesterol in the aortic wall in cholesterol-fed rabbits despite having no effects on plasma cholesterol levels. Subsequent experimental MI in these animals showed smaller infarcts in the BM 13.505-treated group. Farafi et al. showed that the development of atherosclerosis in monkeys results in a increased sensitivity of large cerebral arteries to the vasoconstrictive effectsof U-46,619,384thereby perhaps offering an explanation for the increased susceptibility to thrombotic episodes. Other beneficial effects of TXA, receptor antagonists on the vasculature include the ability of SQ 29,548 to improve canine arterial graft patency.% Elevation of TxB2 levels have been observed in mice following injection of CCb. In this model of liver disease, the observed increases in serum GOT and GPT were mimicked by the administration of U-46,619, supporting the hypothesis that TxA, mediates CCb-induced liver injury.386 TxA, displays a number of effects in the gastrointestinal tract, some of which appear to be at odds with one another. The stable TxA,/PGH, mimic U-46,619 was reported to inhibit gastric acid secretion in isolated rat mucosa.

-


557

In contrast to this result (which could be interpreted that TxA,/PGI-I, might reduce gastric lesion development), close arterial injection of U-46,619-induced (100-500 mg/kg/min for 10 min) damage in the rat mucosa. In this study, the gastric damage was reduced by pretreatment with BM 13.177 (5 mg/kg, i.v.)=; however this antagonist was completely ineffective in preventing gastric lesions induced by a number of noxious agents.389 Several studies suggest that TxA, may also effect intestinal function. Alemayehu and Chou reported that U-44,069 (stable TxA,/PGH, mimic) reduced jejunal wall blood flow in the anesthetized dog which was inhibited by SQ 29,54tL3%These investigators also demonstrated that the food-induced increase in intestinal capillary fitration coefficient (Kfc) and oxygen uptake were enhanced by SQ 29,548.391Direct effects were also noted on ion transport; U46,619 stimulated Cl--secretion and inhibited Na+ and Cl-absorption, effects which were inhibited by SKF 88,046.392

H. TxA,-Dependent Responses of Various Endogenous Mediators Many of the studios outlined in the above sections have described the ability of TxA, receptor antagonists to inhibit or block the sequelea following administration of PGH2, TXA,, or stable TxA,/PGendoperoxide mimics. As shown in Table XIII, the effects of a number of endogenous agonists are mediated, at least in part, through synthesis of TXA, and subsequent activation of the TxA,/PGendoperoxide receptor. For example, some of the effects of plateletactivating factor (platelet s e c r e t i ~ nb, r~o~n c h ~ s p a s m renal , ~ ~ hemodynamics395,3%), endothelin-1 (contraction of rat aorta3w),angiotensin-I1 (decrease in GFR,398,399), substance P (contraction of canine pulmonary veinm), and chemotactic peptide (contraction of human umbilical arteriesM1)can be blocked by specific TxA, receptor antagonists. VI. CLINICAL STUDIES A. TxA, in Human Pathophysiology

Support for a causative role for TXA, in human pathophysiology must await clinical trials with specific, long-acting receptor antagonists. There is evidence, however, that elevated TxA, levels are found in disease states in which the TxA, present could be responsible for some of the clinical dysfunctions observed. Other compounds may also interact at the TxA2 receptor. The major metabolite of PGD,, 9cyllf3-PGF2exhibits full TXA, agonist activity in the rabbit jugular vein and caused platelet shape change, both of which could be inhibited by BM 13.177.TXA, metabolite levels were elevated in women with moderate to severe pregnancy-induced hypertension with median excretion levels of 3919 pg/mg creatinine vs. 927 pg/mg creatinine for control patients.16The increased 2,3dinor-TxB, excretion correlated with mean arterial blood pressure, platelet count, and plasma lactate dehydrogenase. In a related study, there were no differences in TxA, metabolite levels between normals and hypertensives, however, there was a marked reduction in PGI, metabolite levels in which there was a significant negative correlation between PGI, metabolite levels and mean blood pressure.403Support for a causative role of TxAz in pregnancy-

HALL

558 Table MI1 TxA2-DependentResponses of Various Endogenous Mediators Effect

Antagonist

Ref.

Inhibited platelet-activating-factor (PAF)-induced platelet secretion Inhibited bronchospasm in guinea pigs induced by aerosol PAF Prevented renal hemodynamic effects of PAF in rats

SQ 29,548

393

SQ 30,741

394

SKF 96,148 (BM 13.505) SQ 29,548

395 396

SQ 29,548

615

SQ 29,548 AH 23,848 SQ 29,548

616 617 618

SQ 29,548 Ono-3708 AH 23,848 R-68,070 SQ 29,548

619 620 621

L-670,596

622 623

SQ 29,548

624

SQ 29,548

625 626

SQ 29,548

627

SQ 29,548

628

SQ 29,548

629

13-APA

630

13-APA

631

SQ 29,548

400

Ono-3708

632

BM 13.177

633

Blocked f-Met-Leu-Phe-induced contractions of human umbilical arteries Restored the normal endothelium-dependent relaxation to ACh in diabetic rabbit aorta Inhibited IP3-induced calcium mobilization in saponinpermeabilized human platelets Inhibited C--induced decrease in dynamic compliance and the increase in pulmonary resistance in guinea pigs Inhibited the vasoconstrictive response to acetylcholine in the cerebral circulation (newborn pig) and rat aorta Partidy inhibited the increase in mean arterial blood pressure (MAP) and abolished the decrease in glomerular filtration rate (GFR) induced by i.v. angiotensin I1 (AII) in the rat Attenuated the monoclonal antithymocyte antibodyinduced decrease in GFR and renal blood flow (RBF) and inhibited the increase in LTB4 synthesis Abolished hypoxic venous constriction in isolated lamb lungs Inhibited the decrease in pO2 and 0 2 delivery, and pulmonary vasoconstriction induced by lipid infusion in newborn pigs Abolished the audiogenic seizure-shock episode in acute Mg-deficient weanling rats Inhibited LPS-induced enhancement of the pulmonary hypertension and edema following PAF stimulation Blocked the effects of cell-directed inhibitor of monocyte leukotaxis (CDI-MLx) Inhibited heparin-induced platelet aggregation in human platelet-rich plasma Inhibited neutrophil-induced increase in vascular permeability in hamsters Inhibited substance P-induced contraction of canine pulmonary vein Inhibited nicotine-induced contraction of canine cerebral artery Attenuated the edema and Dulmonarv vasoconstriction induced by AII in isolated rat lungs

614

398 399


559

induced hypertension (PIH) came from two trials in which low dose (60 mg) aspirin treatment resulted in longer pregnancies and increased weight of newborns.404This dose of aspirin resulted in nearly complete inhibition of maternal serum TxB2 production with only a 63% inhibition in the neonate. Another study demonstrated that 100-mg aspirin resulted in a significant reduction in the number of women who developed PIH (12%vs. 36%)and preeclamptic toxemia (3%vs. 23%).405 However, aspirin is contraindicated in late stages of pregnancy. Thromboxane A2 may also be involved in the regulation of human fetoplacental circulation. Vascular resistance in the isolated fetal cotyledon was increased by U-44,069 (inhibited by SQ 29,548) but interestingly, PGE2, PGF2,, and PG12 had no effect in this vascular bed.= Elevated TxA2 synthesis in vivo has been observed in type I1 hypercholesterolemics in whom urinary 11-dehydro-TxB2levels correlated with platelet aggregabilit~.~~ Increased TxA2production has also been observed in unstable angina patients408and type 1[Refs. 409-4111 but not type 2 diabetic^.^" Likely more important than the absolute level of TxA2synthesis is the ratio of TxA2 synthesis relative to PG12 production. An increase in the TxB2/PG12ratio was noted in patients on cyclosporin A, suggesting that excess TxA2production might be responsible for the observed hypertension and thrombotic events associated with this therapy.413Rectal biopsy specimens from patients with Crohn's disease showed an increase in the TxB2/PG12ratio, which could lead to altered cytoprotective capacity.414 The rationale that thromboxane synthase inhibition would result in increased PG12production has not been uniformly supported in the clinic. Using CGS 13080, Vesterqvist observed no change in urinary PGI2 metabolites despite a 7540%inhibition of TxA2 synthesis.14In contrast, Fitzgerald observed concomitant increases in PG12from a bleed wound which was coincident with decreased synthesis of TxA2.l6 Transient platelet aggregation has been demonstrated during evolution of unstable angina.415Dorn et al. observed an increase in TxA2receptor numbers in patients with acute myocardial infarction and that the receptor numbers was greatest in patients with prolonged ischemic chest pain.416Elevated TXA, levels have also been observed in cardiopulmonary bypass where Ono-3708 ameliorated the renal dysfunction associated with this procedure.417 The development of TSI and TRAs for treatment of stroke has been a primary focus of Ono's development program; indeed, the first approved indication for a TSI has been for subarachnoid hemorrhage. A physiological basis for this comes from a study in which vessels from patients with cerebral ischemia were shown to be hyperresponsive to the stable TxA2analog, STA2.418 It has been shown that the vascular effects of the prostaglandins PGD2 and PGF2, are mediated in part through the TxA2 receptor. Daily analysis of cerebrospinal fluid in five patients with aneurysmal subarachnoidhemorrhage revealed that concentrations of PGF2, correlated with the development and fluctuations in clinical v a s o ~ p a s mIf. ~the ~ ~effect of PGF2, is mediated via the TxA2 receptor, one would expect a TRA to be more effective than a TSI in this setting. Industry interest in these agents can also be gauged by the use patents which have been published. These include the use of TxA2 receptor antagonists for cyclosporin-induced nephrotoxicity ( G l a x ~ " ~ ~ ~myocardial ~'),

HALL

560

stunning (Squibbm), dysmenorrhoea (National Development Research C~rp."~),pulmonary hypertension following adverse protamine/heparin interaction (SquibbQ4), migraine (Squibbm), pregnancy-induced toxemia (Squibb,Q6 GlaxoQ7), skin injury (SquibbtQ8), myofibroblast function (Glaxoa9), and coronary angioplasty (Glaxom). Other use patent applications include combinations of receptor antagonists with (a) thrombolytic agents to prevent reocclusion (Glaxotal SKBa2), (b) thromboxane synthase inhibitors for enhanced efficacy in occlusive vascular disease ( G l a x ~ , ~ , ~ IC1435),(c) phosphodiesterase inhibitors for thrombosis (Thomae K GmBHmra7), prostacyclin analogs (Schering AGU8), and (d) calcium channel blockers for ischemia (Squibba?. B. Clinical Status of TxAz Receptor Antagonists

Of the multitude of TxAz receptor antagonists described, only a handful have advanced to clinical trials. Definitive evidence for a role of TXA,in human pathophysiology remains elusive as only several Phase I1 pilot studies with BM 13.177 and GR 32,191 have been published. Comparison of these limited results with those generated with TxA2synthase inhibitors suggests that TxA, receptor antagonists may offer more promise as clinical therapeutics.440Intravenous infusion of BM 13.177 for 48 h resulted in a sigruficant increase in renal blood flow in patients with diffuse proliferative lupus nephritis.360BM 13.177 was also effective in preventing restenosis in grafted vessels following bypass, however, this level of protection did not exceed that of ASA.441In contrast to these beneficial effects, a pilot study with BM 13.177 in unstable angina had to be discontinued due to the development of myocardial ischemia in 50% (2 of 4) of the drug-treated group. It is not clear whether the ischemic event was triggered by the drug or from withdrawal of previous medication. GR 32,191 afforded partial inhibition of allergan-induced bronchoconstrict i ~ n , suggesting ~ , ~ ~ that an antagonist to a single mediator may not be suitable for asthma therapy. AA-2414, which possesses multiple pharmacologies, was 80% effective in controlling asthma when given at a dose of 40 mglkg, P . O . ~Further references to clinical trials are compiled in Table XIV. VII. FUTURE DIRECTIONS

It has been only in the last several years that truly potent TxA, antagonists have been developed that are completely free of agonistic activity. These highly specific receptor antagonists should establish the relative importance of TxAz in human disease. Given the recent patent activity, it is likely that future synthetic efforts will focus on receptor antagonists of extended duration of action (suitable for once-a-day dosing) and receptor antagonists that also possess other activities such as thromboxane synthase inhibition, histamine antagonism, and serotonin antagonism. The author especially thanks Dr. M.L. Ogletree for his critical reading of the manuscript and for his suggestion to include Table MIX, for which he provided most of the references. The author also thanks Dr.P.W. Sprague and Dr.D.M.Floyd for their support during the preparation of this manuscript, and Ms. Caroline Coleman for typing the tables.

Bayer AG Bcehringer Mannheim; SKB

442,443,637644

Phase 3 (U.K.)

Glaxo

GR 32,191 (vapiprost)

Bay u 3405 BM 13,177 (sulotroban)

635, 636

discontinued

Glaxo

Phase 1 Phase2 (Europe) Phase 2 (U.S.)

angioplasty, cyclosporin-induced nephrotoxiaty; asthma; deep vein thrombosis

441,646459

645

634

AH 23,648

adjuntive therapy with thrombolysis

Phase 1 (U.S.)

squibb

65

!3Q 30,741

discontinued

Ref(@.

Squibb

Indication

SQ 28,668

status

Company

Antagonist

Table M V Clinical Status of TxAz Receptor Antagonists

Development terminated, presumably due to teratageniaty in mice; no effect (70mg p.0.) in stable angina; reduced platelet deposition on vascular grafis[6361 Inhibited both platelet and vascular effects[637] of U-46,619; synergistic effect with heparin on bleeding time[638]; partial inhibition of allerganinduced bronchoconstriction[442,443]; bleeding time unaffected by coadministration of nitrates[641]; equally effective to heparidwarfarin therapy in preventing restenosis after thrornbolysis[642]; Phase 1 studies[643]; interaction trial with cydospoMe[644] Pharmacokinetics Continuous infusion in lupus nephritis patients resulted in increased insulin clearance rate[647]; pharmacokinetics in renal failure patients[648, 6501; resting myocardial ischemia after infusion[6491; pharmacokinetics[651); (continued)

Development halted after Phase I studies; superceded by SQ 30,741; pharmokinetic studies[B]

Comments

8 +

m

E

2 8z 8

Phase 1 Phase 2

Phase 1 Phase 2

ICI Janssen

Shionogi Takeda

ICI 192,605 R-68,070 (R-70,416; sodium salt) S145 AA-2414

Phase 1

Ono

Ono-8809

Ono-3708

Phase 1 (Europe) Phase 1 (U.S.) Phase 2 (i.v. only)

status

Boehringer Mannheim; SKB Ono

Company

BM 13,505 (daltroban)

Antagonist

asthma

acute respiratory distress; cardiopulmonary bypass cerebral infarction; asthma; nephritis

Indication

Table XIV Continued

444

667

665 214, 666

664

662,663

660,661

Ref@).

80% effective in controlling asthma

Pharmacokinetics studies Reduced plasma PTG levels in patients with obstructive arterial disease[214]

Increased free-water clearance in cirrhotic patients with ascites[663]

combination with TSI increased bleeding time prolongation[652, 6531. No difference in restenosis when compared to ASA-treated group[441]; not effective in combination with TSI in cold-induced vasoconstriction; effects in atherosclerotic patients[&]; reduced vein graft occlusion in bypass surgery[655]; reduced time to lysis when given in combination with streptokinase or t-PA[656]; pharmacokinetics in elderly[657]; reduced graft occlusion rate (3.1% vs. 11.5%)[658]; not effective in preventing reocclusion following coronary angioplasty[659] Multiple dose pharmacokinetics[571]; single-dose pharmacokinetics[584]

Comments

r r

$2

CJl


563

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prostaglandin H2 receptor antagonists.

Potent, long-acting cyclopentane-1,3-Dione thromboxane (A2)-receptor antagonists.

Experimental and clinical action of thromboxane A2 receptor antagonists.

Differences in activities of thromboxane A2 receptor antagonists in smooth muscle cells.

Non-prostanoid thromboxane A2 receptor antagonists with a dibenzoxepin ring system. 1.

Expression of thromboxane A2 receptor gene and thromboxane A2 synthase in bovine corpora lutea.

prostaglandin endoperoxide receptor in rabbit platelets.

Thromboxane A2 synthesis in pregnancy-induced hypertension.

Thromboxane A2 synthesis in human erythroleukemia cells.

transglutaminase-2 binding to thromboxane A2 receptor.

Prevention of Ca(2+)-induced or thromboxane B2-induced hepatocyte plasma membrane bleb formation by thromboxane receptor antagonists.

Thromboxane A2 receptor (TBXA2R) is a potent survival factor for triple negative breast cancers (TNBCs).

Inverse agonism of SQ 29,548 and Ramatroban on Thromboxane A2 receptor.

BAY u3405, a potent and selective thromboxane A2 receptor antagonist on airway smooth muscle in vitro.

Cloning and expression of cDNA for a human thromboxane A2 receptor.

Glibenclamide is a competitive antagonist of the thromboxane A2 receptor in dog coronary artery in vitro.

Role for the thromboxane A2 receptor β-isoform in the pathogenesis of intrauterine growth restriction.

Pathophysiology of isoprostanes in the cardiovascular system: implications of isoprostane-mediated thromboxane A2 receptor activation.

prostaglandin H2 receptor antagonistic activity of phenol derivatives.

Synthesis of metabolites of S-1452, an orally active thromboxane A2 receptor antagonist.

prostaglandin H2 receptors.

Mouse thromboxane A2 receptor: cDNA cloning, expression and northern blot analysis.

The effects of thromboxane receptor antagonists on oestrogen-induced uterotrophic responses in the spontaneously hypertensive rat.

Thromboxane A2 exacerbates acute lung injury via promoting edema formation.