TiPS - November

1992 IVol. 131

12 Marks, M. J. and Collins, A. C. (1982) Mol. Pharmacol. 22,554-564 13 Clarke, P. 8. S., Schwartz, R. D., Paul, S. M., Pert, C. B. and Pert, A. (1985) J. Neurosci. 5, 1307-131s 14 Schneider, M., Adee, C., Betz, H. and Schmidt, J. (1985) 1. Biol. Chem. 260, l4505-14512 . 15 Loring, R. H. and Zigmond, R. E. (1988) Trends Neurosci. 11, 73-78 16 Ravdin, P. M. and Berg, D. K. (1979) Proc. Nat1 Acad. Sci. USA 76,2072-2076 17 Miller, M. M. and Billiar, R. B. (1986) J. Pineal Res. 3,159-168 18 London, E. D., Connolly, R. J., Szikszay, M. and Wamsley, J. K. (1985) Eur. 1. Pharmacol. 110,391-392 19 Marks, M. J., Stitzel, J. A. and Collins, A. C. (1985) J. Pharmacol. Exp. Ther. 235, 619-628 20 de la Garza, R., McGuire, T. J., Freedman, R. and Hoffer, B. J. (1987) Neuroscience 23, 887-891 21 de la Garza, R., Freedman, R. and Hoffer, J. (1989) Neuropharmacology 28, 495-501 22 Hunt, S. P. and Schmidt, J. (1978) Brain Res. 157,213-232 23 Conti-Tronconi, B. M. et al. (1985) Proc. Nat1 Acad. Sci. USA 82,5208-5212 24 Kemp, G. E., Bentley, L., McNamee, M. G. and Morley, B. J. (1985) Brain Res. 347,274-283 25 Whiting, P. and Lindstrom, J. (1987) Proc. Nat1 Acad. Sci. USA 84,595-599

413 26 Gotti, C. et al. (1991) Proc. Nat1 Acad. Sd. USA 88,3258-3262 27 Schoepfer, R., Conroy, W. G., Whiting, I’., Gore, M. and Lindstrom, J. (1990) Neuron 5, 35-48 28 Couturier, S. et al. (1990) Neuron 5, 847-836 29 B&to, L. R. G., Keyser, K. T., Lindstrom, J. M. and Karten, H. J. (1992) /. Comp. Neural. 317, 325-340 30 Anand, R., White, M. and Lindstmm, J. (1991) Sot. Neurosci. Abstr. 17, 105.5 31 McLane, K. E., Wu, X. and ContiTronconi, B. M. (1991) Biochemistru 30, 10730-10738 32 Wada, E., McKinnon, D., Heinemann, S., Patrick, J. and Swanson, I.. W. (1990) Brain Res. 526,45-53 33 lohnson, D. S., Stroessnez -Johnson, H. M., Boulter, J., Amaral, D. G. and Heinemann, S. (1991) Sot. Neurosci. Abstr. 17, 105.3 34 Revah, F. et al. (1991) Nature 353, 846-849 M., Pereira, E. F. R., 35 Alkondon, Wonnacott, S. and Albuquerque, E. X. (1992) Mol. Pharmacol. 41,802-808 36 Zorumski, C. F., Thio, L. L., IsenberE, K. E. and Clifford, D. B. (1992) Mol. Pharmacol. 41,931-936 37 Alkondon, M. and Albuquerque, E. X. (1991) J. Recept. Res. ll, lOOl-1021 38 Listerud, M., Brussaard, A. B., Devay, P., Colman, D. R. and Role, L. W. (1991) Science 254,1518-1521

Development of GPllbAlla antagonists as antithrombotic drugs Andrew J. Nichols, Robert R. Ruffolo, Jr, William F. Huffman, George Poste and James Samanen Thrombosis represents a major target for development of drugs to prevent and treat a variety of cardiovascular and cerebrovascular diseases, which are the leading cause of morbidity and mortality in the Western world. This review by Andy Nichols and colleagues focuses on a central process in thrombosis, namely platelet aggregation, and how it can be inhibited by antagonists of the adhesion molecule GPZZblZZZa. Successful and future therapeutic applications of GPZZb/ZZZaantagonists, and their pharmacology, are considered in detail. Thrombosis is the pathological extension of the normal haemostatic process that is required to prevent blood loss following damage to the vascular wall. Red thrombi, which have little or no platelet A. I. Nichols is Associate Fellow in Cardiovascular Pharmacology, R. R. Ruffolo, ]r is Vice President and Director of Pharmacological Sciences, W. F. Huffman is Director of Piptidomimetic Research, -6;. Paste is President and Chairman of Research and Developmenf Technologies, and 1. Samanen is Associate Director in Peutidomimetic Research, SmifhKline Beechan; Pharmaceuficals, 709 Swedeland Road, King of Prussia, PA 19406, USA.

component, are found in areas of low shear stress, such as the deep veins. White and mixed thrombi, which have a significant platelet component, are associated with endothelial damage in regions of high shear stress, such as in the region of a ruptured atherosclerotic plaque in a coronary artery. In such cases of damage, thrombosis is initiated by platelet adhesion to von Willebrand factor, and to collagen and other matrix proteins in the exposed subendothelium. Adhesion of platelets to collagen and

39 Schoepfer, R., Halvorsen. S. W.. Con&y, W. G., Whiting, P. and Lindstrom, J. (1989) FEBS Lett. 257. 393-399 40 Vemino, S., Amador, M., Luetie, C. W., Patrick, J. and Dani, J. A. (199!!) Neuron 8,127-134 41 Mulle, C., Choquet, D., Kom, H. and Changeux, J-P. (1992) Neuron 8,l35-143 42 Vijayaraghavan, S., Pugh, P. C, Zhang, Z., Rathouz, M. M. and Berg, D. K. (1992) Neuron 8,353-362 43 Jacob, M. H. and Berg, D. K. (1983) J. Neurosci. 3, 260-271 44 Arimatsu, Y., Seto, A. and Amano, T. (1978) Brain Res. 147,165-X9 45 Hunt, S. P. and Schmidt, J. ;,*a) Brain Res. 142, i52-159 46 Clarke, P. II. S., Hamill, G. S., Nadi, N. S., Jacobowitz, D. M. and Pert, A. (1986) J. Comp. Neural. 251,407Al3 47 van de Kamp, J. L. and Collins, k C. (1992) Pharmacol. Biocbem. Behav. 42, 131-141 48 Afar, R, Clarke, P. 8. S., Goldstein, G. and Quik, M. (1992) Neuroscience 48, 641-653 49 Quik, M. (1992) Mol. Neurobiol. 6,1-20 50 Pauly, J. R., Grun, E. KJ. and Collins, A. C. (1992) in The Biology of Nicotine: Current Research Issues (Lippiello, P. M., Collins, A. C., Gray, J. A. and Robinson, J. H., eds), pp. 121-137, Raven Press 51 Nelson, L. (1978) Fed. Proc. 37, -2.547

von Willebrand factor activates the platelets and causes release of second messengers (e.g. thromboxane AZ) and secretion from granules (of, for example, ATP, 5-I-E, platelet-derived growth factor, transforming growth factor and fkhromboglobulin), and catalyses the conversion of prothrombin to thrombin on the platelet surface, alI of which act to produce platelet aggregation in the region of the adherent platelets. Aggregation is associated with further granule release, which amplifies the thrombotic process and may also initiate vascular remodelling in the region of the thrombus. Platelet aggregation is therefore an important target for research into antithrombotic drugs, and one aspect that has recently received much attention is the role of GPIIb/IIla. GPlIb/lIIa is a member of the integrin family of adhesion molecules which are comprised of two glycoproteins, an a-subunit and a g-subunit, joined in a noncovalent complex (Fig. 1). Role of GPIIHIIIa The critical role of Gl?IIb/IIIa in platelet aggregation is exemplified in patients with Glanzmann’s @ 1992, Elaevier

Science Publishm

Ltd (UK)

TiPS -November 1992 [Vol. 131

414

two y chains (Fig. 1). The regions of fibrinogen that are responsible for binding to GPIIb/IIIa are residues 95-97 and 572-574, both representing RGD sequences in the (Y chain, and the 12 Cresidues, 400-411 terminal (HHLGGAKQAGDV), in the y chain’. It appears that only the RGD sequences closer to the Nterminal (i.e. 95-97) are involved in binding solution- hase fibrinogen to GPIIb/IIIa PO. Even if fibrinogen is not the major mediator of platelet aggregation in vivo, von Willebrand factor also has an RGD sequence that binds to GPIIb/IIIa. In receptor crosslinking experiments, RGD peptides have been found to bind to residues 109-171 of GPIIIa (Ref. ll), whereas y chain dodecapeptides have been found to bind to residues 294-314 of GPIIb (Ref. 12). The interaction of fibrinogen with GPIIb/IIIa to cross-link adjacent platelets is shown in Fig. 1. Interestingly, RGD peptides and y chain peptides compete at GPIIb/ IIIa suggesting some functional interaction between these two binding sites13.

l/kezneshowrrdots, RGDset#tJemsrir#elK~andin

blue@ihetzamhal12intim?ydmin.

tlwmbasthenia, in which there is a congenital defect or deficiency in intact GPIIb/IIIa on the platelets’. Platelets from these patients fail to bind fibrinogen and do not aggmgau?. Since solution-phase fibrinogen and other macromolecules bind to GPIIb/IIIa only after platelet activation3, and the molecular defect in Glanzmann’c thrombasthenia is a loss of functional GPIIb/IIIa, it can be concluded that a change in conformation in GPIIb/IIIa following platelet activation allowing the interaction of macromolecules is an absolute requirement for platelet aggregation. Thus, this process is the final common pathway for platelet aggregation and, therefore, represents a target for pharmacological intervention to inhibit platelet aggregation produced by all stimuli. RGD as an adhesive motif The peptide sequence Arg-GlyAsp (RGD in single-letter code), originally recognized as the adhesive motif in fibronectin*, is also present’ in fibrinogen, von Willebrand factor and vitronectin5, the circulatory macromolecules that are believed to mediate plate-

let aggregation. As such, small RGD-containing peptides inhibit binding of fibrinogen to activated platelets, and inhibit platelet aggregatior@. Although fibrinogen is usually assumed to be the plasma macromolecule responsible for platelet aggregation’, there is evidence that von Willebrand factors may also be involved, at least under certain conditions. Fibrinogen is a symmetrical multimeric protein that consists of two (Y chains, two l3 chains and

RGD analogs The first GPIIb/IIIa antagonists to be developed were monoclonal antibodies, such as 7E3 (Ref. 14). However, using monoclonal antibodies as therapeutic agents may present many problems. Thus, many groups have concentrated on developing small-molecule GPIIb/IIIa antagonists. Shebuski et aZ.15 demonstrated that direct intracoronaiy infusion of acetylArg-Gly-Asp-Ser-NHz could inhibit platelet-dependent coronary

TABLE 1.Structurally modified analogs of Arg-Gly-Asp-Ser and their potency and selectivity as GPllWllla antaoonists

SirWtWtl?

Ac-Arg-Gly-Asp-Ser-NH, Ac-Arg-Gly-Asp-Val-NH, Ac-Cys-Arg-Gly-Asp-Cys-NH* Ls !3J Ac-Cys-Arg-Gly-Asp-Pen-NH2 l-S SJ Ac-CT-(NMe)Ag-Gly-Asp-Pen-NH, S-l (sKeSFto6760) Mba-@Me)Arg-Gly-Asp-Man

LseJ

ADP-induced platelet aggregation* K&l w 91.3 55.5 16.2

L8 cell binding to vitroneotlnf tcw (WI 150

Selecfivtfy for GPllb/llla~ 1.64

4.1 0.35

67.2

192

0.09

2.0

22

ISK&FlORGOI

lConcentration required to produce 60% inhibition in canine platelet-rich plasma. TConcentration required to produce 50% inhibition. L6 cells are a rat skeletal muscle cell line. *Relative to L6 cell vitroneotin receptor.

TiPS - November 1992 [Vol. 131 artery thrombosis, but that high doses were required and the duration of action was short. Thus, the approach taken by most groups has been to de\...!op analogs of RGDs in an attempt to increase affinity for GPIIb/IIIa, reduce affinity for other RGD-dependent integrins, and to increase plasma stability. Only limited data are so far available on the activity of the many compounds that have been synthesized. SK&F106760 and SK&F107260 (Table I) are RGD analogs with constrained conformations that impart higher affinity for GPIIW IIIa and greater stability to degradation by plasma peptidases. Table I shows the progressive increase in affinity for GPIIb/IIIa, and increasing antiaggregatory potency, as acetyl-Arg-Gly-AspSer-NH2 is modified by increasing the lipophilicity of the N-terminal region, constraining the conformation within a cyclic disulfide structure, and methylation of the arginine u-amino group. In contrast to the increase in affinity for GPIIb/IIIa, these modifications do not increase affinity consistently for the vitronectin receptor on the LB skeletal muscle cell line (Table I), thus leading to selectivity for GPIIb/IIIa.

Therapeutic applications of GPIIb/IIIa antagonists Since thrombosis is the major cause of a variety of cardiovascular cerebrovascular diseases, and there are many potential therapeutic applications of GPIIb/IIIa antagonists. These include the treatment and prevention of unstable angina, acute myocardial ischemia infarction, transient attacks and stroke, and as adjuvants to thrombolysis.

415

BlOOd

lr..,, CVLL_.a-L

200

presswe (mm W 2:

Heart rate (beats min-‘1 1 -- --

g&,

$Q

\...._,(jf\,.i-_ + SK&F106760 (1.0 mg kg-’ iv) ..

Fig. 2. Effect of SK&F10376o on ptatetet-dependent wronary artery thmmtmsis. Platelet-dependent thmmbosis is produced in an endothetiat damaged @ft chum&x wronary artery (LCX) in the presence ofasfenosispmdumdbyanea?etWf.UaHc cylinder placed around the coronaryartery As thmmbosis pnx%e&, the vessef is graduatty occluded and wronary artery flow de&es. When the thmmbus tit@ occludes the vessel wronary artery flow is reduced to zero and the p&tic cytfn& is moved up and down the vessel to mechanic&y shake loose (SL) the thmmbus. The thrombus is allowed to reform and the process is repeated to pmduce a series of platelet-dependent cyclic coronary artery flow mktionS. SKBFlG3750 produces an immediate and wmptete inhibition of rhe cyck wronary artery flow mducttons wkhout producing any effect on arteriat blood pressureor heart rate.

with a very high degree of stenosis, can be dislodged mechanically to give rise to transient cyclic reductions in coronary artery blood flow. SK&F106760 and SK&F107260 abolish the cyclic reductions in blood flow that are produced in endothelial damaged coronary arteries in the presence of a high-grade stenosis (shown in Fig. 2). When administered at doses that produce at least 90% inhibition of ex vivo platelet aggreGPIIb/IIIa antagonists gation, always inhibit platelet-dependent coronary artery thrombosis. In contrast, as irin is not effective in all animals P6. Figure 3 shows such an animal in which aspirin failed to inhibit the coronary artery cyclic flow reductions. In contrast, SK&F106760 abolished the cyclic flow reductions.

In animals that am responsive to aspirin, thrombosis can be reinduced by increasing the degree of stenosis, such as occurs with acute rupture or haemorrhage into an atherosclerotic plaque, or chronic progression of atherosclerosis, or by mild elevation of plasma adrenaline level@. In contrast, when the cyclic flow reductions are abolished by a GPIIblIIIa antagonist they cannot be reinduced by increasing the degree of endothelial damage or by infusion of adrenaline14. These data demonstrate two important phenomena. First, aspirin is not universally effective at inhibiting platelet-dependent coronary artery non-cyclosince thrombosis, platelet oxygenase-dependent aggregation commonly occurs in vivo. Secondly, GPIIb/IIIa antagonists are universally effective

Unstable angina

An animal model of unstable angina has been developed by Folts, in which platelet-dependent coronary artery thrombosis is produced by endothelial damage of a coronary artery in the presence of a high-grade stenosi#‘. Under these conditions, coronary artery blood flow is reduced as the platelet-rich thrombus forms in the and of the stenosis region gradually occludes the vessel. This thrombus can dislodge spontaneously or, under conditions of marked endothelial damage and

blood pressure

aspirin

SK&F106760

F/g. 3. Contrasting effects of the cyctwxygenase inhibitor aspirin (5mgkg-‘, iv) and the GPllb/hla anfagonist SKbFltI375g (0.3mgkgs-i, i.v.) on platetet-dependent cyckc wmnaty amy flowreductionsin an anaesthetied dog.

as anti-platelet agents in oino, since they inhibit the final common pathway of platelet aggregation. and they work under conditions in which aspirin is ineffective. Thus, although aspirin is effective in the treatment of unstable angina, a GPIIb/fffa antagonist maybeexpectedtobemoreeffectime since activity would still be evident following acute rupture of the atherosclerotic plaque or chronic progression of the atherosclerotic lesion. Pmuenfion @acute ntyocardial i@TCliOtl If left

untreated, unstable angina often pmgresses to acute myocardial i&&ion in which the coronary artery thrombus is sufficiently huge and stable to produce myocardial ischaemia sufficient to produce irreversible infamtion. The nature of the coronary artery thrombus in patients that die from such episodes has been shown to consist of a platelet-rich head with a fibrWe@rocy@rich tail”, suggest&g a role for platelets in the initiation, and perhaps the pmgmssion, of such thrombi. The morphology of the blood vessel and the thrombus both strongly suggest an important role for platelets in acute myocardial Warction. Clinical studies with aspirin support this hypothesis. For example, in the Physician’s Health Study involving over 22,tHM physicians in the US, aspirin treatment over a period of five years reduced the annual incidence of acute myocardial infarction by 44%‘ from 0.4% to 0.2% (Ref. 18). fu anaesthetized dogs, GPfJbIlffa antagonists reduced the incidence and magnitude of fibrin/platelet-dependent thrombi produced by electrolytic damage to the endothelium of the left &cumflex coronary artery in the presence of a critical, eccentric stenosi!L Mickelson et a1.‘9 demonstrated that, in this model, the 7E3 mon~on~ antibody prevents acute thrombotic occlusion of the coronary artery, and reduced the fibrin/platelet thrombus mass. This was accompanied by a reduction in the deposition of plate&s to the damaged vascular endothelium and within the formed thrombus that corresponded with au inhibition of ex vioo platelet aggregation.

Similarly, SK&F106760 significantly reduces the formation of fibrin/platelet thrombi and reduces the incidence of occlusive thrombo&“. The precise mechanism by which GPflb/IIla antagonists prevent coronary artery thrombosis is unknown, but probably involves inhibition of the aggregation on platelet damaged vessel and of the formation of the prothrombinase complex on the platelet surface by inhibition of platelet aggregation. The Pe~tine-Aspen Re(PARIS-II) infarction Study demonstrated that one year following an initial myocardial infarction, aspirin (in combination with ~p~d~ole) reduced the coronary event rate (reinfarction and death) by 48% in patients who had suffered an initial lowseverity non-Q-wave myocardial i&r&ion, but in patients with an initial high-severity Q-wave infarct, the reduction was only 7% (Ref. 21). Thus, in patient populations in which coronary artery disease is more severe, aspirin does not appear to have any significant benefit. This is analogous to the decrease in efficacy of aspirin to inhibit platelet-dependent coronary artery cyclic flow reductions in the Felts model as the degree of stenosis becomes more severe. Thus, in view of the efficacy of GPllb/IfIa antagonists in preventing acute rnyoc~~~ inf~~on in experimental animal models and the maintained efficacy of GPllb/Illa antagonists under conditions where aspirin becomes ineffective,

GPIIblIIIa antagonists may turn out to be significantly more effective than aspirin in the primary and secondary prevention of acute myocardial infarction in patients with more advanced coronary artery disease.

Adjuvantsto thrombolysis One of the major goals in thrombolytic research is to enhance the overall efficacy of coronary thrombolysis by increasing the incidence of reperfusion and eliminating reocclusion. One approich is to increase the efficacy of currently available thrombolytics. The thrombolytic profile of tissue plasminogen activator (@A) or streptokinase can be enhanced by concomitant administration of a GPIlb/llla antagonist in canine

models of coronary thrombosis in which the thrombus consists

primarily meshed in significant For exam antibod $

of erythrocytes ena fibrin network with a platelet component. le, the 7E3 monoclonal

the snake venom peptide, bitist&in” and the RGD peptide, SK&F106760 (Ref. 20) increase the incidence of, and reduce the time to, reperfusion, and decrease the rate of, and time to, reocclusion. The importance of preventing reocclusion following coronary thrombolysis has been demonstrated in an analysis of nearly 1000 patients receiving thrombolytic therapy for acute myocardial infarction. Thrombolysis was achieved with tPA, urokinase, or a combination of both, and all patients received current optimal therapy, including aspirin. Inhospital mortality rate was increased 2&fold, and recovery of global and infarct zone cardiac function was significantly impaired, in patients in whom coronary artery thrombolysis was followed by coronary artery reocclusion’*. The study concluded that reocclusion following successful reperfusion was associated with substantial morbidity and mortality rates and that new strategies to prevent reocclusion, such as GPIIblIIIa antagonists, need to be developed. Transientischaemic attacks and &Yoke

Cerebral transient ischaemic attacks are associated with extracrani21 carotid artcry 0iyease25c an& there is a history of previous attacks in app~ximately 75% of patients with a completed strokez6. The cause of transient ischaemic attack is believed to be transient thrombosis in the region of stenosis, followed by cerebral embolization. The critical role of platelets in these attacks and subsequent progression to stroke is demonstrated by clinical studies of aspirin and ticlopidine, in which both agents have been demonstrated to reduce significantly the incidence of stroke in high-risk patient8’. In a canine model of extracranial carotid artery disease, SK~l~760 inhibits thrombosis and subsequent stroke in 100% of animals with stenosed, endothelialdamaged carotid arteries2s. In contrast, aspirin was effective in only

EPS - November

1992 [Vol. 131

33% of the animals. Moreover, in those animals in which aspirin prevented carotid arterial thrombosis, inLl.easing the degree of stenosis rendered the aspirin ineffective”. These data suggest that GPIIb/IIIa antagonists may be significantly superior to aspirin in the prevention of stroke in highrisk patients.

Future directions Intravenous administration of monoclonal antibody or peptide GPIIb/IIIa antagonists would be suitable for the acute treatment of cardiovascular and cerebrovascular diseases. However, for chronic therapy for primary or secondary prevention of thrombotic diseases, such compounds would not be appropriate due to their relatively short duration of action and poor oral bioavailability. Thus, nonpeptide GPIIb/IIIa antagonists are required. For example, a recently reported compound, [[[4(4-amino-iminomethyl)-N-methylbenzamido)-acetyl]-oitho-phenyleneldioxyldiacetic acid29, inhibits human platelet aggregation with an I&, of 301~ but with no activity at vitronectin receptors up to

Easy steps in organic chemistry Aromatic

Heterocyclic Chemistry

by David T. Davies, Oxford Science Publications, 1992. E4.99 p&k (88 pages) ISBN 0 29 855660 8 There is a multitude of choice available for a lecturer to select a general first-year undergraduate chemistry textbook to organic recommend to his or her students; it is a matter of selecting the style, presentation and organization of material that you prefer, or that best matches the course. When it comes to some (second/thirdyear) topics, however, the relevant chapters in these general texts are inadequate, if they exist at all. Heterocyclic chemistry is one such topic. The next step up has usually been to a more specialist text, but these very often contain much

417 100 urvr.Thus it can only be a matter of time before a potent, selective, orally active GPIIb/IIIa antagonist is found.

References 1 Phillips, D. R. and Agin, P. P. (1977) J. Clin. Invest. 60, 535-545 2 Mustard, J. F., Kinlough-Rathbone, R. L., Packham, M. A., Perry, D. W. and Pai, K. R. M. (1979) Blood 54,987-993 3 Bennet, J. S. and Vilaire. G. (1979) J. Cfin. Znvesf. 64,1393-1401 4 Pierschbacher, M. D. and Ruoslahti, E. (1984) Nufure 309,30-33 5 Ruoslahti, E. and Pierschbacher, M. D. (1984) Science 238,491-497 6 Plow, E. F., Pierschbacher, M. D., Ruoslahti, E., Marguerie, G. and Ginsburg, M. H. (1985) Proc. Nafl Acad. Sci. USA 82,8057-8061 7 Hawiger, J., Kloczewiak, M., Bednarek, M. A. and Timmons, S. (1989) Biochemistry 28,290%2914 8 Weiss, H. J. et al. (1989) J. Cfin. Invest. 83.288-297 9 Kloczewiak, M., Timmons, S., Lukas, T. J. and Hawiger, J. (1984) Bfochemisfry 23,1767-1774 10 Cheresh, D. A, Berlinger, S. A., Vicente, V. and Ruggeri, Z. M. (1989) Cell 58,945-953 11 D’Souza, S. E. et al. (1988) Science 242, 91-93 I2 D’Souza, S. E., Ginsburg, M. H., Burke, T. A. and Plow, E. F. (1990) J. BioZ. Chem. 265,~3446

more material than is found in the average course unit, and are consequently too big and expensive to make it easy for a student to go out and buy them. Enter the Oxford Chemistry Primer series - books that set out to contain the right amount of material to act as companion to an 8-10 lecture course on a gigen topic. As one who teaches a course in heterocyclic chemistry of just that length, 1 support wholeheartedly the objectives of this series of books, and was thus very see heterocyclic pleased to chemistry feature early in the the series. After all, despite limited length of the typical relevant course unit, this area of chemistry produces a very high of all published proportion organic chemistry and is of fundamental industrial importance. This series has another serious

13 Timmons, S., Bednarek, M., Ktocmwiak, M. and Hawiger, J. (1989) Biochemisfy 28,2919-2923 14 Caller, B. S., Felts, J. D., Scudder, L. E. and Smith, S. R. (1986) Bfood68,783-786 15 Shebuski, R. J. et al. (1989) Thromb. Haemosf. 61.183-188 16 Felts, J. (1991) Circulation 83 (Suppl. IV), 3-14 17 Constantinides, P. (1966) JOAfheroscler. Res. 6,1-W 18 The Steering Committee of the Physician’s Health Study Group (1989) N. Engl. J. Med. 3l2,l29-135 19 Mickelson. J. K.. Simpson, P. J. and Lucchesi, 8. R. (1989) J. Mol. cell. Cardiol. 21, 39M 20 Nichols, A. J. et al. (1990) Eur. J. Pharmacol. 183,2019 21 KIimt, C. R., Knatterud, G. I., Stan&r, J. and Meier, P. (1986) J. Am. CoZZ.Cardiol. 7,251-259 22 Gold, H. K. et al. (1988) Circufizfion 77, 670-677 23 Shebuski, R. J., StabiIito, I. J,, Sitko. G. R. and Polokoff, M. H. (1990) Circulation 82,169-177 24 Ohman, E. M. et aZ. (1998) Circulation 82, 781-791 25 Rosenberg, N. (1989) in Z&&book of carotid arfey su&y~ Facfs and figure& pp. 31-44, CRC Press 26 Hass, W. K. et ul. (1989) N. EngZ.I. Med. 321,501-507 27 Gent, M. et al. (1989) Lancef i, 12154220 28 WiIIette, R. N. et aZ. (1992) Sfroke 2% 703-711 29 ABig, L., EdenboIer, A., MuIIer, M, Trzeciak, A. and Weller, T. (1998) European Patent No. EP 381486

advantage - it sells for a realistic price to be a personal purchase for a chemistry undergraduate (the low price is made possible by industrial sponsorship). Does this book fulfil the expectations that I had of it? It most certainly does! The author has managed, in only 88 pages, to distil the essence of the area and present it in a very readable fashion. The approach is modem, with emphasis on synthesis and mechanism; the ‘black art’ of heterocyclic synthesis, often a stumbling block for students in the past, is analysed in current retrosynthetic thinking. The style of writing is clear and straightforward; each individual section is short enough to be read, rather than to be used just as a reference work. The detailed content is pretty much what I wanted to see; after an introduction to the area and the principles inretrosynthetic volved, the five-membered ring systems are discussed, starting with the simple pyrroles, thiophenes and furans, and moving to