AMPA receptor-positive allosteric modulators for the treatment of schizophrenia: an overview of recent patent applications.

Future

Review

For reprint orders, please contact [email protected]

Medicinal Chemistry

AMPA receptor-positive allosteric modulators for the treatment of schizophrenia: an overview of recent patent applications The role of glutamate and its receptors in central nervous system biology and disease has long been of interest to scientists involved in both fundamental research and drug discovery, however the complex pharmacology and lack of highly selective compounds has severely hampered drug discovery efforts in this area. Recent advances in the identification and profiling of positive allosteric modulators of the AMPA receptor offer a potential way forward and the hope of a new treatment for schizophrenia. This article will review recent patent applications published in this area.

AMPA receptor structure, function & role of positive allosteric modulators Glutamate is the principle neurotransmitter in the central nervous system responsible for excitatory signaling. It acts through two distinct classes of receptors (Figure 1) : ionotropic (ion channels: NMDA, AMPA and kainate subtypes) and metabotropic (G-protein coupled receptors: mGluR1–8 subtypes), the former of which are responsible for the fast, excitatory signaling. The ionotropic receptors are classified according to agonists originally identified to discriminate between them, namely N-methyl-d-aspartate, α-amino-3hydroxy-5-methyl-4-isoxazole-propionic acid and kainate [1] . The AMPA receptors are tetrameric receptors comprised of subunits GluA1–4 (formerly GluRA-D or GluR1–4). These subunits arise from four genes encoding approximately 900 amino acids, for which the derived proteins have approximately 65–75% sequence homology with each other [2] . The subunits are glycosylated and are made up of an amino terminal domain, an agonist or ligand binding domain, a transmembrane domain and an intracellular domain. The amino terminal domain contains binding sites for regulatory proteins and shares amino acid sequence homology with the bacterial periplasmic binding proteins. The agonist or ligand binding domain is made up of two polypeptide domains, S1 and

10.4155/FMC.15.4 © 2015 Future Science Ltd

Simon E Ward*,1, Lewis E Pennicott1 & Paul Beswick1 1 Translational Drug Discovery Group, University of Sussex, Falmer, Brighton, East Sussex BN1 9QJ, UK *Author for correspondence: [email protected]

S2 which form the clamshell motif into which glutamate binds. Furthermore, all AMPA receptor-positive modulators, that have generated protein-ligand crystal structures, have been found to bind within this domain. The transmembrane region comprises three transmembrane sequences M1, M3 and M4 and a reentrant loop M2, which forms a quarter of the pore forming region in the full tetrameric receptor. Finally, the intracellular domain contains binding sites for a range of regulatory and trafficking protein interaction sites [3] . Functional AMPA receptors can be created from a range of subunit combinations. This structural diversity is further increased by the presence of sites of posttranslational modification and alternative splicing. In particular, one of the ligand binding domains exists in two splice forms (known as flip and flop) impacting the biophysical properties of the channel, and the R/Q site within the pore of GluA2 controls the calcium permeability of the subunit. This R/Q site is present as a glutamine in development, but is edited to arginine in the mature brain, which serves to essentially render the ion channel comprising R GluA2 permeable to sodium and potassium ions but not calcium ions. A wide range of studies has demonstrated that the AMPA receptor subunits are distributed unevenly throughout the mammalian brain. In particular, there are high levels of

Future Med. Chem. (2015) 7(4), 473–491

part of

ISSN 1756-8919

473

Review Ward, Pennicott & Beswick

Primary excitatory neurotransmitter in CNS

Glutamate

Major glutamate receptor classes

Receptor subtypes

Metabotropic receptors

Ionotropic receptors

NMDA GluN1; 2A-D

AMPA GluA1-4

Kainate GluK1-5

mGluR1-8

Figure 1. Main classes of glutamate receptors.

expression of all subunits except GluA4 in the rat and macaque hippocampus, amygdala, basal ganglia, lateral septum and outer cortical regions. GluA4 itself shows highest expression in the cerebellum [4–6] . In addition to these gross anatomical divisions, there is also considerable differentiation in cellular expression within the various brain regions. The understanding of the structure and assembly of the AMPA receptor subunits has been advanced significantly over recent years with pivotal data generated from single particle electron microscopy [7] analysis and x-ray crystallography [8] . In particular, the publication of the structure from x-ray diffraction data at 3.6 Å resolution of the full length GluA2 rat receptor homomeric tetramer bound to a competitive antagonist, ZK200775 was a significant landmark (Figure 2) [9] . This information, combined with many early studKey terms Glutamate (glutamic acid): Naturally occurring and biologically active amino acid which occurs widely throughout the body and is present in many parts of the central nervous system. AMPA: α-Amino-3-hydroxy-5-Methyl-4-isoxazolePropionic Acid a compound which selectively activates a subset of glutamate receptors. Allosteric modulator: Substance that indirectly influences the activity of an endogenous biologically active compound at its target protein. Allosteric modulators may be either positive modulators which enhance the response of the natural ligand or negative which reduce the response. NMDA: N-Methyl d Aspartic acid a compound which selectively activates a subset of glutamate receptors, this subset is distinct from that selectively activated by AMPA. Schizophrenia: Long-term mental health condition that causes a range of different psychological symptoms, including hallucinations, delusions, cognitive impairment and changes in behavior.

474

Future Med. Chem. (2015) 7(4)

ies on higher resolution structures of isolated domain constructs has enabled a detailed understanding of the link between structure and function of the AMPA receptor [10] . Furthermore, this understanding has been applied to the discovery of new modulators described below [11,12] . Additionally mutagenesis experiments have helped further understand the binding mode and how this influences the mechanism of action of positive allosteric modulators of the AMPA receptor [13] . The AMPA receptor mediates the majority of fast excitatory signaling within the mammalian CNS. During periods of repetitive stimulation, the AMPA receptor mediates relief of the voltage-dependent magnesium ion block of the NMDA receptor, allowing it to also contribute to the fast excitatory signaling, and also allowing influx of calcium ions. This influx then drives a range of downstream intracellular events leading to induction of synaptic plasticity, including the processes of long-term potentiation and long-term depression (LTP and LTD), that are believed to underlie the deposition of memory [14,15] . The response elicited by glutamate on the AMPA receptor is a direct consequence of its subunit composition (and further splice variations / posttranslational modifications). This variation is observed as differences in the kinetics of deactivation (ion channel closure with release of glutamate) and desensitization (ion channel closure with glutamate still bound), the latter occurring extremely rapidly on the timescale of ion channels, typically within 10 ms of activation. In addition to the complexities in the AMPA receptor subunit composition, there are many additional factors that need to be considered for a full understanding of the kinetics and properties of the function of these ion channels. Of particular importance is the presence of accessory proteins which interact with motifs present on the C-terminal domain. These structural motifs

future science group

AMPA receptor-positive allosteric modulators for the treatment of schizophrenia

Review

ATD

LBD

Out

TMD

In 150 Å Figure 2. Structure of AMPA receptor. Subunit chains are colored differently (In/Out refer to interior/exterior of cell). ATD: Amino terminal domain; LBD: Ligand binding domain; TMD: Transmembrane domain. Adapted with permission from [9] © Nature Publishing Group (2014).

can phosphorylate the transmembrane AMPA regulatory proteins (TARPs) and interact with additional classes of accessory proteins such as cornichon proteins CNIH-2 and CNIH-3, all which serve to regulate AMPARs by increasing their expression and altering receptor kinetics [16,17] .


Clinical rationale for targeting AMPA receptors in schizophrenia Schizophrenia is a devastating disease which manifests across a range of positive (e.g., hallucinations), negative (e.g., withdrawal, apathy) and cognitive symptoms. It affects approximately 1% of the adult

www.future-science.com

475

Review Ward, Pennicott & Beswick population with onset in early adulthood. Current therapies for schizophrenia are centred on antagonists of the dopamine D2 receptor, with many other pharmacological actions present in all drugs. Over recent years, the glutamate dysfunction has emerged as a strong hypothesis for the development of new hypotheses to treat schizophrenia. Indeed, glutamatergic dysfunction may be of particular importance in schizophrenic patients with severe negative symptoms and impairment of executive function and memory [18] . There exists a considerable body of empirical evidence to link glutamate to schizophrenia. Studies of patients with schizophrenia show a reduction in glutamate neurotransmission, a decrease in CSF glutamate concentrations and a reduction in post mortem hippocampal glutamate. These changes are potentially linked to reductions in glutamate carboxypeptidase II leading to an increase in N-acetyl-aspartyl glutamate which acts as an endogenous glutamate receptor antagonist. Considerable additional evidence from receptor expression studies, radio-labeled binding studies and immunocytochemistry have generally confirmed these observations, although no appropriate tools are yet available to generate in vivo data [19,20] . Additional strong evidence comes from the observations of NMDA receptor blockers such as ketamine and phencyclidine or PCP, which can induce a state similar to schizophrenia in otherwise healthy individuals and also exacerbate the disease in schizophrenic patients. Furthermore, blocking NMDA receptors impairs cognition in animal and human studies. Supporting this, radiolabeled AMPA binding studies show that AMPA binding increases in the rat brain in relevant brain regions following learning episodes and artificial increase or decrease of AMPA receptor subunit populations has a positive or negative effect respectively on cognitive tasks in rodents [21,22] . Additionally, recent publications have sought to marry modulators of both NMDA and AMPA demonstrating cognition enhancing effects in mice [23] . AMPA receptor-positive modulators Given the association of glutamate signaling dysfunction with a number of psychiatric and neurological disorders, many approaches have been investigated to generated ligands for the various glutamate receptors with varying degrees of subtype selectivity within and between family members. Furthermore, these ligands have been of diverse modes of action – agonist, antagonists and allosteric modulators (positive and negative). Following the disease rationale above, increasing glutamatergic tone would be of interest in many disease states; however, the use of direct AMPA agonist or partial agonists, which have been extensively researched and described,

476


is unlikely to be of direct therapeutic benefit due to the significant risk of toxicity derived from overexcitation. In particular, a global increase in glutamate receptor signaling will be unable to maintain the precise and refined spatial and temporal control of activation that enables accurate processing of information. To overcome this hurdle, many groups have focused efforts on discovery of AMPA receptor-positive allosteric modulators which can either reduce the rate of desensitization of the receptor or slow the rate of deactivation to achieve an increase in ion flux through the channel upon binding of glutamate. Importantly, this approach maintains the spatial and temporal control of activation [24,25] . Many classes of AMPA receptor-positive allosteric modulator have now been described (see description of chemotypes below) and the molecules generally potentiate glutamate-mediated AMPA receptor currents with limited subunit selectivites, but excellent selectivity against the other glutamate receptor families, NMDA, kainate and mGluRs. These receptor modulators have demonstrated potentiation of AMPA currents in a variety of settings, both recombinant and native tissue cell preparations and in hippocampal slices, for which marked increases were observed in polysynaptic facilitation compared with monosynaptic facilitation, consistent with the expected cooperative amplification across synaptic networks [26,27] . AMPA receptor allosteric modulators have also been shown to enhance long-term potentiation (LTP), increase brain-derived neurotrophic factor (BDNF) and improve cognition in a diverse range of memory and learning tasks in a wide range of species [28] . The large volume of data demonstrating relevant biochemical responses together with preclinical efficacy provides confidence that compounds currently undergoing clinical evaluation should be able to demonstrate positive effects. In addition to the considerable potential for cognitive enhancement, preclinical data have also been reported suggesting a role for AMPA receptor allosteric modulators in the treatment of addiction [29] , neurodegeneration [30] , ADHD [31] autism [32] and exercise-induced fatigue [33] among others. Clinical landscape There are several distinct classes of AMPA receptorpositive allosteric modulators (Figure 3) that have been investigated in clinical studies [34–52] . A summary of clinical trials reported on these compounds to date is given in Table 1, while a number of molecules have progressed to Phase II studies, disappointingly none have yet entered wider population Phase III trials. Furthermore, despite a number of trials still listed as on-going, it is likely that the majority of these trials are no longer being actively pursued.



O

O N

N

O

O

O

3, CX691, ORG2448

2, CX516

H N

NH

H

N H

Cl

N

N

O S

S

N

O

N

H2N

N

N

N

O

1, aniracetam

5, cyclothiazide

H

O

O

O

O O O S N H

O

N H

HN

F

N

O

N

8 [11]

S

N CF3

10, PF-4958242

O

7, LY450108

N

CN

S

O

F

S NH

H N

O

O O

H

4, ORG26576

F

O

O

S

6, LY451395

O

Review

O

H N

S Cl

O

S O

N O

11, Diazoxide

9 [41] Figure 3. Clinically evaluated AMPAR-positive modulators.

The initial set of AMPA receptor modulators to enter clinical trials were those derived from aniracetam (1), the original nootropic agent whose study led to the interest in the design of new, more potent modulators. This work was driven by Lynch and others initially from the University of California and subsequently from Cortex to derive molecules CX516 (2), CX691 (3) and others. These initial molecules set high expectations following early positive clinical signals in healthy volunteers, elderly volunteers and schizophrenia patients [34–36] . However, these initial positive data were then superseded by negative data for both the original CX516 (2) [37–39] and the newer, more potent molecules. From this chemical class, Phase II trials have been registered for schizophrenia, fragile X [38] , autism [38] , depression [41] , cognition enhancement [37] , cognitive impairment in schizophrenia (as stand alone or adjunct) [35–36,42] , ADHD [44] , drug-induced respiratory depression [45] . Data published by Cortex [46] , from a small study with their current lead compound, CX1739, shows a hint of efficacy on some symptoms of sleep apnea. Cortex are currently understood to be focusing on testing the potential of this compound to treat opiate induced respiratory depression, based on statements which appeared on the company website [47] during 2014. Subsequent chemical series focused on the phenethylamine sulfonamide scaffold have afforded


several molecules. Lilly progressed LY451395 (Mibampator (6)) into Phase II which was reported negative for improving the cognitive deficits in Alzheimer’s disease (AD) [49] . A subsequent study investigating the potential to treat aggression and agitation in AD also failed to show significant benefit [50] and the molecule no longer appears in Lilly’s development portfolio. This series has then yielded molecules from GlaxoSmithKline (8, 9) [11,54] and Pfizer (10) [53,55] which have entered Phase I evaluation. Summary of recent developments in the patent literature 2008–2014 There have been some excellent reviews of the patent literature over the recent years with the most recent from Pirotte et al. [56] . The intention of this review is to cover the developments in the patent literature from 2008–2014. Table 2 summarizes patents published during this period with representative structures from each patent. A number of general observations can be made from studying the table and the references cited therein. Firstly, the majority of the patents were filed during the earlier part of the time period covered indicating that perhaps activity in this area has reduced in recent years, indeed this is supported by the fact that only one compound; PF4958242 is reported to be currently


477


Table 1. Brief summary of clinical trials for AMPA receptor-positive allosteric modulators. Molecule

Trial

Status

CX516 (Ampalex)

Cognitive performance in healthy young and aged volunteers

Improved cognitive performance

Ref.

CX516 added to clozapine, olanzapine or risperidone in patients Inconsistent cognitive benefits with schizophrenia

[35,36]

Completed

[37]

Effects of CX516 on functioning in fragile X syndrome and autism Completed

[38]

Treatment of Alzheimer’s disease with CX516

Completed

[39]

Cardiac safety study of PhI and PhII ORG24448 patients

95 patients completed

[40]

Depression 8 week treatment, includes PET analysis Excluded patients with propensity for seizure following EEG assessment

180 patients completed

[41]

TUNRS NIMH-funded cognitive impairments in schizophrenia 8 weeks adjunctive therapy to existing atypical antipsychotic medication

Terminated

[42]

DARPA-funded small scale trial in healthy volunteers subjected to simulated night shift work

No improvement in cognitive performance

[43]

ADHD small (n = 23–28) study of 200 mg bid and 800 mg bid for 3 weeks in adults with moderate-severe symptoms

Significant improvements at highest dose on hyperactivity and inattention indices

[44]

Drug-induced respiratory depression

[45]

CX1739

Sleep apnea

No effect on mean apnea/ hypopnea index, however significantly reduced apnea time

[46]

ORG26576

Phase II major depressive disorder 54 patients Part 1: 100–600 mg bid up to 16 d Part 2: 30 subjects; high dose group and low dose group. 28 d dosing

Completed

[48]

ADHD 60 patients 100–300 mg BID; 8 weeks

Completed

[49]

Aggression and agitation in AD 132 patients; 3 mg bid 12 weeks

Comparable to placebo on all endpoint except Frontal Systems Behavior Inventory where a significant improvement was demonstrated (p = 0.007)

[50]

AD 200 patients

Negative

[51]

GSK729327

Ph I 79 volunteers, 1–6 mg

Completed

[52]

PF-4958242

Ph I Ten studies currently registered

On-going

[53]

CX691 (ORG24448/ SCH900460/ Faramaptor) CX717

LY451395 (Mibampator)

Efficacy and safety of CX516 In elderly participants with mild cognitive impairment

[34]

in active development. The reason for the decline in activity is not clear, but it maybe a consequence of many pharmaceutical companies withdrawing from the neuroscience area in recent years despite significant medical unmet need. Secondly the majority of the

478


more recent patents have been published by academic groups, maybe suggesting that interest in AMPA as a therapeutic target remains high but there has been a shift from research efforts being centered in pharmaceutical companies to academic laboratories. Finally



the chemistry has focused on roughly four main chemotypes as discussed in the previous section, the reasons for this are not clear however this does suggest that the chemotypes are amenable to considerable structural modification which retains activity. GlaxoSmithKline have filed extensively in this area with 12 patents in the period covered by this article, the last being in 2010 [57–68] . Within the earlier patents GlaxoSmithKline describe N-Aryl trifluoromethylindazole derivatives and trifluoromethyl pyrazoles all containing an amide function in the para position of the aromatic ring [57–61] . Pyrazoles and fused pyrazoles are a common functionality in AMPA receptor-positive modulator structures which have appeared in the patent literature during this period. All of the patents have a relatively narrow scope exemplified by a range of closely related analogues and for some examples primary in vitro data are provided. Subsequently Glaxo-

Review

SmithKline have published more detailed information on the pyrazole derivatives [11] which is described in the following section, this work resulted resulted in the development candidate (14, Table 3) . In two later patents [62,63] GlaxoSmithKline claim a series of iminothiazoles and are the only company to have published examples of this chemotype. In the five most recent filings [64–68] GlaxoSmithKline have claimed different series of sulphonamides, these chemotypes build on publications prior to 2008, the discovery of which has been described in the scientific literature [54] , a series which also produced a development candidate (15; Table 3) . Takeda have filed six patents between 2009 and 2012, each containing having a very broad scope and containing many examples [69–74] . Four patents [69–72] cover trifluoromethylpyrazoles and related fused bicyclic ring systems. The pyrazoles claimed are similar to those which appear in GlaxoSmithKline’s

Table 2. Patents covering AMPA receptor-positive modulators published between 2008 and 2014. Research institution

Chemotype

GlaxoSmithKline

Indazole/Pyrazole derivatives

Representative structures and associated patent references

O

O

N

O

O

S

N

NH N

N

N

N

N

N

N N

CF3

CF3 CF3

[57]

(14) [59]

[58]

O O N N

N

N

N

N N

CF3 CF3 [60]

[61]

Thiazolidineimines

HO F N

N S O

S

O

O N

[62]


O N

N

N

[63]


479


Table 2. Patents covering AMPA receptor-positive modulators published between 2008 and 2014 (cont.). Research institution

Chemotype

Sulphomamides

Representative structures and associated patent references

N O

O

O

O

O

O

S NH

S NH

S

NH

O [64]

[65]

F

O

O

HN S

S NH

O

O

O

O

[66]

[67]

O

O

S NH

N

O [68]

Takeda

Bicyclic derivatives

O

N N

N O

O

N

N

CF3

CF3

CF3

[70]

[71]

Cl

HN O

O

O

N N

N

O S O

N

CF3

[72]

Pyran suplhonamide

O

N

N

N

N NH

N

[69]

N

F3C

N

N

N

[73] N

S

O O

HN

S

O

O

[74]

480




Review


Chemotype

Pfizer

Sulphonamides

Representative structures and associated patent references F

F

N

HN

S O

HN S O

O O [91]

O [90]

N

O

S

N OHHN S

O

O

O

O

O

HN S

O

S

[93]

O

[92]

Organon

O

S

F 3C

O

HO

NH2

S NH

N N

NH

O

[95] O

N N

O

F3C N

N

HO

CF3

N

S

N H

[94] [96] CF3

O

O

S NH

N [97]

Cortex

Tricyclic scaffolds

O N N

N

N

F

O

N

N

O

N

N

O

N O

O [99]

[98] N N

N

N

O N

N

N

N

N O

N

N

N

N

N

(20) [100]



481



Chemotype

Sevier

Bicyclic sulphonyl scaffolds

Representative structures and associated patent references O

O S

HN

F

O

O O S N

[101]

O O S

N

N O

[102]

N

O

HN

O

HN

Br

N

N H

O O S

O

[103]

O O S

S O

N

O [104]

University of Salento

[105]

Cyclothiazide derivatives

O H N Cl

O

S

NH

O

[106]

University of Texas

Azaindoles

H N

O

N

S

O

N

[107]

Columbia University

Biphenyls

H N

H N O S O

S

O O O O S N H

Zapolsky Eduardovich

Dimeric structures

N N

N O

O

S

N O N H

N

S [109]

patents, however, in contrast to the GlaxoSmithKline patents which only claim 6-membered aromatic groups attached to the pyrazole ring nitrogen, Takeda claim a wide variety of substituents. In most cases and in common with GlaxoSmithKline an amide is claimed in the preferred group in upper region of the molecules. In a later patent Takeda [73] describes analogues of the benzothiadiazine chemotype such as 3, 4-dihydropyrido [2, 1- c] [1,2,4]] thiadiazine 2,2-dioxide, little data are provided to indicate if this unusual bicyclic group is related to the fused pyrazoles claimed earlier


(LY451646)

N

H N O

482

N

[109]

[110]

O

or represents a distinct series of AMPA receptor modulators. This was followed by a later patent [74] claiming sulphonamides derived from cycloalkyl and heterocycloakyl amines the scope of which is again very broad includes the tetrahydropyran derivatives shown in Table 2. Very little biological data are provided in the Takeda patents and unlike many other pharmaceutical companies they have yet to publish any medicinal chemistry or pharmacology papers. Pfizer have focused their efforts on analogues of the phenethyl sulphonamide chemotype related to com-



pounds also claimed by Takeda, and published four patents between 2008 and 2010 [90–93] . Their initial filing in 2008 [90] contains cyclic sulphone sulphonamides in contrast to their 2010 patents [91–93] which focused on tetrahydrofuran/tetrahydropyran sulphonamides. The tetrahydrofuran/tetrahydropyran sulphonamides all have a syn biaryl left hand side which is either connected directly to the tetrahydrofuran/ tetrahydropyran or via an ether linker. In one case [91] compounds are exemplified which have a tertiary alcohol present at the junction of the biaryl system and the

Review

tetrahydrofuran/tetrahydropyran motif. All four patents have a broad generic scope exemplified by a small number of examples for which primary in vitro biological data is provided. Compound 10 is believed to be the development candidate PF-4958242 (reported to be in Phase I studies at the time of writing) and is exemplified in reference [92] . Organon have filed four patents between 2008 and 2010 which focus on the trifluoromethylpyrazole chemotype [94–97] . In their initial patent [94] which has a narrow scope they claim tetrahydroindazoles con-

Table 3. Chemotypes described in the scientific literature 2008–2014. Research organization Chemotypes

Ref.

Pfizer

N

NH S O O O

[75,76]

NH N

O

O

S O

N

S

HN

SO2

N

N F

O

F

(11)

PF-04701475 (12)

GlaxoSmithKline

O

[11,54]

N O

O

S NH

N N

F

N

N (15)

CF3

(14)

Merck/Organon

O

S

[77,78] NH

N H

O

S

NH2

NH NH

O

N N

O

N H N

CF3 (16)

Lilly in collaboration with Universities of Colorado and Atlanta

PF4778574 (13)

(17)

N CF3 [79]

NH O S O

O

S O HN (18) N

N

S HO

S O

O

OH

(19)



483


Table 3. Chemotypes described in the scientific literature 2008–2014 (cont.). Research organization Chemotypes

Ref.

Cortex

O

N N

N

N

N

N

O

N

N

N

N

N

O

N

N

O

N

O2N N

[80–83] N

N

O O

O

N

(21)

N

(22)

O

N

N

N

N

(20)

N

O

O

O

N

N

N

N

O O

(23)

Servier alone and in collaboration with Universities of Copenhagen and Liege

O O S HN

O O S HN

[84–86]

F

N N S 18986 (24)

(25)

O

O O S HN

O

N (26)

University of Modena

O O S HN

Cl

O O S NH

Cl

N H

N H

Me

(28)

O

(27)

[87,88]

O O S NH2

Cl

NH2 (29)

University of Texas and Northwestern University

Me O

S

O

N N

O

(30) Me

N O

[89]

H N

H N O

N

S O

(31)

484




nected to a tetrahydrobenzthiophene group through an acyclic linking group. The patent is limited to the specific two bicyclic heterocycles which are variously substituted off the amide group. Two subsequent patents [95,96] claim ring opened indazole versions in which a 3-trifluoromethyl – 4- hydroxymethyl pyrazole group appears to be one of the preferred substitution patterns. In these cases the scope is much broader and a variety of monocyclic 5-membered heterocyclic rings are claimed, and these in turn are attached to a diverse set of groups in one case [95] the preferred group being an indane sulfonamide previously disclosed by GlaxoSmithKline. In the most recent patent [97] the Organon group describe compounds in which the pyrazole appears to have been replaced by a phenyl group. Cortex have published a further three patents during 2008–2009 [98–100] which exemplify benzotriazine analogues. The first two patents [98,99] focus on a common tricyclic core with having an oxazinone ring fused to the benzotriazine. The first patent [98] has broad scope focussing on diverse groups appended to the nitrogen of the benzoxazinone as depicted by the example in table in vitro electrophysiology data is given for key examples. The second patent [99] has a much narrower scope and focuses on a single example, the fluorophenyl compound shown in Table 2 for which in vivo data are given and the compound produces an increase of evoked potentials (EPSPs) in an anesthetized rat at a dose of 5 mg/Kg. The third claim [100] generically covers tricyclic structures derived from both benztriazininones and benzpyrimidinones with a second benztriazininone or benzpyrimidinone ring fused to the core phenyl group although the majority of examples contain two triazinone rings (20) as depicted in Table 2. Servier’s research has been focused on analogues of benzothiadiazines with five patents published between 2010 and 2012 [101–105] . They have explored the saturated benzothiadiazines and also a 1 carbon homologated ring system as well as substituting nitrogen atoms for oxygen or carbon. The first patent [101] covers phenoxy benzthiadiazepines as depicted the claim is specific to this ring system and the patent exemplifies analogues substituted on either nitrogen atom and/or the pendant phenyl ring some limited electrophysiology data are given for key examples. The second patent [102] covers N-cyclopropyl benzothiadiazenes, a wide variety of examples are exemplified with different substituents on the phenyl ring with electrophysiology given for a limited set of compounds. Further cases [103–105] cover further variations on the phenoxybenzthiadiazepines in which the heterocyclic ring has been modified, the scope of these patents is very simi-


Review

lar in structure to the earlier case [101] and in vitro data is given on key examples. The University of Salento published 1 patent in 2012 [106] covering both saturated and unsaturated benzothiadiazines similar manner to those described by Servier [101–105] . The scope of the patent is limited to the single core heterocyclic ring system shown in Table 2. In vitro electrophysiology data are presented in which compounds modulate the response of the AMPA receptor when treated with kainite. Interestingly the compound shown in Table 2 behaves as a positive allosteric modulator, where the oxidized version (the compound having a double bond between the nitrogen and the sulfonyl group) shows negative allosteric modulation. The University of Texas has published one patent [107] in 2013 containing structures based on the phenethyl sulphonamide chemotype. The scope is very broad being based on a phenylalkyl sulfonamide substituted with an azaindole or indole at the 4- position, the scope allows the indole or azaindole to bear a wide variety of substitution. Columbia University published one patent in 2010 [108] . In this patent the authors describe the design of symmetrical dimeric compounds based on the observation of the binding mode of LY451646 (Table 2) in Xray crystal structures with the AMPA receptor. They inferred that the compound was capable of binding in two modes with the sulphonamide making the key interactions and proposed that the dimeric sulphonamides would be more potent than LY451646. In the patent electrophysiology data and in vivo data is presented to support the hypothesis. The scope is narrow limited to a biaryl core with a narrow range of alkyl sulphonamides attached only at the positions shown in the example. Zapolsky Eduardovich has published two patents in 2012 which contain only a small number of compounds [109,110] . These compounds are also symmetrical dimers which have been designed using the similar rational as described by the Columbia group [108] . In vitro data are given on selected compounds to support the claim. Summary of recent journal developments: focus on new chemotypes There has been significant activity in the scientific literature in the area of the medicinal chemistry of AMPA-positive modulators, many of the articles cover templates previously disclosed in patents, however some papers cover novel structures which are not the subject of patent claims. A number of review articles have been published which summarize the general area of medicinal chemistry directed toward AMPA-


485

Review Ward, Pennicott & Beswick positive modulators [24–25,111–112] or focus on specific templates. The reviews are complemented by several focused articles describing specific medicinal chemistry approaches or detailed profiles of advanced compounds. A summary of recently described chemotypes is presented in Table 3. Many of these compounds are currently also covered by patent publications described in the previous section. In a 2013 publication Pfizer describe the detailed pharmacological profile of cyanothiophene PF-4778578 (13) [75] . In vitro the compound is a potent ligand for the AMPA receptor with a binding affinity of 85 nM (rat) and shows positive modulation in a number of cellular assays. In electrophysiology studies using rat cortical neurons it shows a concentration dependent potentiation up to a top concentration of 3 μM. It has an encouraging pharmacokinetic profile across species (rat, dog and nonhuman primate). An extensive range of in vivo studies were performed across a range of species and the compound demonstrated a window between the exposures required for efficacy and those which cause side effects in all cases. Pfizer have also described the discovery via HTS of a series of dihydroisoxazoles (11, 12) [76] and subsequent structure based optimization of a series of dihydroisoxazoles. PF-04701475 (12) is a potent AMPA modulator (EC50 = 123 nM) with a pharmacokinetic profile suitable for in vivo studies in rodent models. Encouraging data were observed with a clear separation between exposures required for efficacy and those which cause convulsions. Further development led to (12) in which the potentially toxic aniline moiety was replaced by a phenyl ring with retention of in vitro potency. GlaxoSmithKline have published details of two development candidates (14,15) [11,54] . The first compound (11), a tetrahydroindazole (14) is derived from a hit identified by HTS and the structure-based optimization from hit to candidate is described, together with the full profile of the candidate. In a subsequent paper [54] GlaxoSmithKline describe the identification off a second development candidate (15) based on an indane template, full details of lead identification and optimization are presented together with human pharmacokinetics. Merck/Organon have published two consecutive articles [77,78] , which describe the identification of a series of tetrahydrobenzthiophenes (16,17) in the first paper [77] they describe the initial optimization of a HTS hit to give a series of AMPAR modulators with micromolar potency (16) but with poor pharmacokinetics. In the following paper [77] they described further optimization which led to (17) a compound which retains micromolar potency but with a pharmacokinetic profile suitable for further profiling.

486


Lilly has described the structure guided design and biological profiles of two symmetrical modulators (18, 19) discovered in collaboration with Universities of Colorado and Atlanta [79] . These compounds were designed from structural information available on the mode of binding of cyclothiazide (5) and the ampakine described by Cortex (2–4). The compounds are structurally distinct but are shown to bind to the same site on the protein and have similar biological profiles. Cortex have reported a two related series of tricyclic compounds [80–83] , a series of benzobistriazinones (20,23) [79 -80] and two papers [82,83] describing benzoxazinones (21,22). Both series demonstrate activity in an in vivo electrophysiology model with compound (20) having an EC50 = 8 nM [80] . The unsubstituted benzoxazinone (21) has weaker activity EC50 = 5uM [80] , modification of the core structure to the lactam (22) allows introduction of substitution on the nitrogen which significantly increases potency [82] (EC50 = 0.7 nM). Further SAR exploration in this region are described in a further paper leading to the tetrazole (23), which is reported to be orally bioavailable in the rat [83] . A number of groups have reported variations of the previously described thiadiazine template. Servier [84] has published further pharmacological information on S 18986 (24). The data package essentially supports its selection as a development candidate detailing in vitro, pharmacokinetic and in vivo efficacy and safety profiles. Servier, in collaboration with workers at the Universities of Copenhagen and Liege, has reported a series of N-alkyl benzthiadiazine derivatives (25) with micromolar potency [85] . A second publication from the University of Liege [86] describes a series of ester derivatives (26). A group at the University of Modena has reported a series of 5–aryl derivatives (27) which shows encouraging in vitro potency (35% potentiation @ 10 μM) and CNS penetration in a mouse study [87] . A subsequent paper from the same group describes the identification of a monocyclic series of AMPAR modulators (29) [88] , based on the observation that the bicyclic compound (28) was unstable and hydrolyzed in the hippocampus to give the monocyclic sulphonamide (29), which was itself an AMPA-positive modulator with modest potency, subsequent SAR studies showed that potency could be improved by attaching small alkyl groups to the aniline nitrogen. Workers at the university of Texas and Northwestern Universities have recently described an informatics approach to identify new AMPA modulators resulting in sulphonamides (30,31) which are reported to have micromolar activity [89] .



Conclusion & future perspective It is clear from the volume of publications within the period covered by this review that interest in compounds which activate the AMPA receptor via allosteric modulation is high. Interestingly there are a number of compounds in clinical evaluation and a number of active discovery projects which suggest that interest will remain for the foreseeable future. It is reasonable to expect the publication of clinical trial data in the next 5–10 years, if any positive results will emerge is difficult to predict. Compounds patented in recent years have different chemotypes and, while it isn’t clearly stated, it is likely that these compounds will have differing modes of action and potentially offer different modalities through which to stimulate the AMPA receptor, it is also likely that in the next 10 years some of these compounds will reach the clinic, thus expectation of positive clinical data in the future remains high. It is interesting to note from publications that an increasing number of academic groups are becoming involved in this area, an observation which reflects current trends in drug discovery research in moving from pharma companies to academic laboratories. With this shift, new direction will potentially be discovered

Review

and explored, and a possible conclusion from this is that the whole area will remain active for the coming decade. Another factor which supports this suggestion is the significant number of reports of the potential for AMPA modulators to treat an increasingly growing number of conditions. In summary it is predicted that this will remain an active area of both preclinical and clinical research over the next decade, with a growing shift from pharmaceutical company-based research to academic drug discovery. Financial & competing interests disclosure S Ward holds a grant from the Wellcome Trust entitled ‘Transforming the treatment of schizophrenia: Design and development of AMPA receptor modulators with a much improved safety profile as novel drugs for treating the cognitive dysfunction associated with schizophrenia and other CNS disorders.’ The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Executive summary • Positive modulators of the AMPA have excellent potential to deliver a new treatment for schizophrenia. • Additionally AMPA receptor-positive modulators have the potential to provide a treatment for a growing number of CNS disorders. • Interest and research activity remains high, this is evidenced by the significant numbers of patents and original scientific articles covered in this review. • New chemotypes have recently been reported, demonstrating further the tractability of the target for drug discovery. • There are a number of compounds under clinical evaluation. The results of these studies, if positive, may lead to new treatments for schizophrenia, but if unsuccessful will offer direction for future studies.

References

6

Beneyto M, Meador-Woodruff JH. Expression of transcripts encoding AMPA receptor subunits and associated postsynaptic proteins in the macaque brain. J. Comp. Neurol. 468(4), 530–554 (2004).

7

Shanks NF, Maruo T, Farina AN, Ellisman MH, Nakagawa T. Contribution of the global subunit structure and stargazin on the maturation of AMPA receptors. J. Neurosci. 30(7), 2728–2740 (2010).

8

Mayer ML. Structure and mechanism of glutamate receptor ion channel assembly, activation and modulation. Curr. Opin. Neurobiol. 21(2), 283–290 (2011).

•

Detailed account the structure function and modulation of glutamate receptors.

9

Sobolevsky AI, Rosconi MP, Gouaux E. X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature 462(7274), 745–756 (2009).

10

Mayer ML. Emerging models of glutamate receptor ion channel structure and function. Structure 19(10), 1370– 1380 (2011).

Papers of special note have been highlighted as: • of interest 1

Kew JN, Kemp JA. Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology (Berl.) 179(1), 4–26 (2005).

2

Collingridge GL, Olsen RW, Peters J, Spedding M. A nomenclature for ligand-gated ion channels. Neuropharmacology 56(1), 2–5 (2009).

3

Chen PE, Wyllie DJ. Pharmacological insights obtained from structure-function studies of ionotropic glutamate receptors. Br. J. Pharmacol. 147, 839–853 (2006).

4

Boulter J, Hollmann M, O’shea-Greenfield A et al. Molecular cloning and functional expression of glutamate receptor subunit genes. Science 249(4972), 1033–1037 (1990).

5

Keinanen K, Wisden W, Sommer B et al. A family of AMPA-selective glutamate receptors. Science 249(4968), 556–560 (1990).



487

Review Ward, Pennicott & Beswick 11

12

13

Pohlsgaard J, Frydenvang K, Madsen U, Kastrup JS. Lessons from more than 80 structures of the GluA2 ligand-binding domain in complex with agonists, antagonists and allosteric modulators. Neuropharmacology 60(1), 135–150 (2011). Weeks AM, Harms JE, Partin KM, Benveniste M. Functional insight into development of positive allosteric modulators of AMPA receptors, Neuropharmacology 85, 57–66 (2014).

14

Gouaux E. Structure and function of AMPA receptors. J. Physiol. 554, 249–253 (2004).

15

Sun Y, Olson R, Horning M, Armstrong N, Mayer M, Gouaux E. Mechanism of glutamate receptor desensitization. Nature 417, 245–253 (2002).

16

Tigaret C, Choquet D. Neuroscience. More AMPAR garnish. Science 323(5919), 1295–1296 (2009).

17

Schwenk J, Harmel N, Zolles G et al. Functional proteomics identify cornichon proteins as auxiliary subunits of AMPA receptors. Science 323(5919), 1313–1319 (2009).

18

Zarate Jr. CA, Manji HK. The role of AMPA receptor modulation in the treatment of neuropsychiatric diseases. Exp. Neurol. 211(1), 7–10 (2008).

modulator, 5-(1-piperidinylcarbonyl)-2,1,3-benzoxadiazole (CX691), in the rat. Psychopharmacology (Berl.) 202(1–3), 343–354 (2009). 29

Watterson LR, Olive, MF. Are AMPA receptor positive allosteric modulators potential pharmacotherapeutics for addiction? Pharmaceuticals 7(1), 29–45, (2014).

30

Lauterborn JC, Pineda E, Chen LY, Ramirez EA, Lynch G, Gall CM. Ampakines cause sustained increases in BDNF signaling at excitatory synapses without changes in AMPA receptor subunit expression. Neuroscience 159(1), 283–295 (2009).

31

Adler LA, Kroon RA, Stein M et al. A Translational approach to evaluate the efficacy and safety of the novel AMPA receptor positive allosteric modulator Org 26576 in adult attention-deficit/hyperactivity disorder. Biol. Psychiatry 72(11), 971–977 (2012).

32

Slverman JL, Oliver CF, Karras MN, Gastrell PT, Crawley JN. AMPAKINE enhancement of social interaction in the BTBR mouse model of autism. Neuropharmacology 64, 268–282 (2013).

33

Fan W, Wu X, Pan Y et al. 1-(1,3-Benzodioxol-5-yl-carbonyl) piperidine, a modulator of α-amino-3-hydroxy-5methyl-4-isoxazole propionic acid receptor, ameliorates exercise-induced fatigue in mice Biol. Pharm. Bull. 37(1), 13–17 (2014).

34

Ingvar M, Ambros-Ingerson J, Davis M et al. Enhancement by an ampakine of memory encoding in humans. Exp. Neurol. 146(2), 553–559 (1997).

35

Lynch G, Granger R, Ambros-Ingerson J, Davis CM, Kessler M, Schehr R. Evidence that a positive modulator of AMPAtype glutamate receptors improves delayed recall in aged humans. Exp. Neurol. 145(1), 89–92 (1997).

36

Goff DC, Leahy L, Berman I et al. A placebo-controlled pilot study of the ampakine CX516 added to clozapine in schizophrenia. J. Clin. Psychopharmacol. 21(5), 484–487 (2001).

37

Chappell AS, Gonzales C, Williams J, Witte MM, Mohs RC, Sperling R. AMPA potentiator treatment of cognitive deficits in Alzheimer disease. Neurology 68(13), 1008–1012 (2007).

19

Albert JS, Wood MW. Targets and Emerging Therapies for Schizophrenia. Wiley-Blackwell, Oxford (2012).

20

Rankovic Z, Bingham M, Nestler EJ, Hargreaves R. Drug Discovery For Psychiatric Disorders. RSC Publishing, Cambridge (2012).

21

Cammarota M, Bevilaqua LR, Bonini JS, Rossatto JI, Medina JH, Izquierdo N. Hippocampal glutamate receptors in fear memory consolidation. Neurotox. Res. 6(3), 205–212 (2004).

22

Akhondzadeh S. The glutamate hypothesis of schizophrenia. J. Clin. Pharm. Ther. 23(4), 243–246 (1998).

•

Original article describing the link between the glutamatergic system and schizophrenia.

38

23

Vignisse J, Steinbusch HW, Grigoriev V et al. Concomitant manipulation of murine NMDA- and AMPA-receptors to produce pro-cognitive drug effects in mice, Eur. Neuropsychopharmacol. 24(2), 309–20 (2014).

Berry-Kravis E, Krause SE, Block SS et al. Effect of CX516, an AMPA-modulating compound, on cognition and behavior in fragile X syndrome: a controlled trial. J. Child Adolesc. Psychopharmacol. 16(5), 525–40 (2006).

39

24

Ward SE, Harries M. Recent advances in the discovery of selective AMPA receptor positive allosteric modulators. Curr. Med. Chem. 17(30), 3503–3513 (2010).

Tolerability and Primary Efficacy of CX516 in Alzheimer’s Disease. https://clinicaltrials.gov/ct2/show/NCT00001662

40

A Follow up Safety Study of Patients Who Participated in Previous Studies of the Drug Org 24448. https://clinicaltrials.gov/ct2/show/NCT00780585

41

Org 24448 to Treat Major Depression. https://clinicaltrials. gov/ct2/show/NCT00113022

42

Org 24448 (Ampakine) for Cognitive Deficits in Schizophrenia. https://clinicaltrials.gov/ct2/show/NCT00425815

43

Wesensten NJ, Reichardt RM, Balkin TJ. Ampakine (CX717) effects on performance and alertness during simulated night shift work. Aviat. Space Environ. Med. 78(10), 937–943 (2007).

25

488

Ward SE, Harries M, Aldegheri L et al. Integration of lead optimization with crystallography for a membrane-bound ion channel target: discovery of a new class of AMPA receptor positive allosteric modulators. J. Med. Chem. 54(1), 78–94 (2011).

Ward SE, Bax BD, Harries M. Challenges for and current status of research into positive modulators of AMPA receptors. Br. J. Pharmacol. 160(2), 181–190 (2010).

26

Arai A, Kessler M, Ambros-Ingerson J et al. Effects of a centrally active benzoylpyrrolidine drug on AMPA receptor kinetics. Neuroscience 75(2), 573–585 (1996).

27

Lynch G. Memory enhancement: the search for mechanismbased drugs. Nat. Neurosci. 5(Suppl.), 1035–1038 (2002).

28

Woolley ML, Waters KA, Gartlon JE et al. Evaluation of the pro-cognitive effects of the AMPA receptor positive




44

Swanson GT. Targeting AMPA and kainate receptors in neurological disease: therapies on the horizon? Neuropsychopharmacology 34, 249–250 (2009).

59

Bradley DM, Chan WN, Harrison SA, Thewlis KM, Ward SE. Compounds which potentiate AMPA receptor and uses thereof in medicine: WO 2008110566A1 (2008).

45

Oertel BG, Felden L, Tran PV et al. Selective antagonism of opioid-induced ventilatory depression by an ampakine molecule in humans without loss of opioid analgesia. Clin. Pharmacol. Ther. 87(2), 204–211 (2010).

60

Bradley DM, Thewlis KM, Ward SE. Compounds which potentiate AMPA receptor and uses thereof in medicine: WO 2008148832A1 (2008).

61

46

Cortex’s AMPAKINE CX1739 Improves Respiratory Parameters in Obstructive Sleep Apnea Patients. www. thefreelibrary.com/Cortex%27s+AMPAKINE+CX1739+I mproves+Respiratory+Parameters+in… -a0248177812

Bradley DM, Chan WN, Ward SE. Compounds which potentiate AMPA receptor and uses thereof in medicine: WO 2008148836A1 (2008).

62

Chan WN, Harrison S, Hughes OR, Neesom JK, Thewlis KM, Ward SE. Compounds which potentiate AMPA receptor and uses thereof in medicine: WO 2009053448A1 (2009).

63

Chan WN, Thewlis KM, Ward SE. Thiazoles which potentiate ampa receptor and medicinal uses thereof: WO 2009053449A1 (2009).

64

Bertheleme N, Chan WN, Scott JS, Ward SE. Compounds which potentiate the AMPA receptor and uses thereof in medicine: WO 2009080637A1 (2009).

65

Thewlis KM, Ward SE. Compounds which potentiate the AMPA receptor and uses thereof in medicine: WO 2009092712A1 (2009).

66

Thewlis KM, Ward SE. Compounds which potentiate the AMPA receptor and uses thereof in medicine: WO 2009092713A1 (2009).

67

Ward SE, Bertheleme N. Compounds which potentiate AMPA receptor and uses thereof in medicine: WO 2010037760A1 (2010).

68

Bradley DM, Cardullo F, Marshall H, Marzorati P, Pozzan A, Ward SE. Compounds which potentiate the AMPA receptor and uses thereof in medicine: WO 2010066658A1 (2010).

69

Mochizuki M, Miura S. Heterocyclic compound: WO 2009119088A1 (2009).

70

Mochizuki M, Imaeda T. Heterocyclic compound: WO 2010140339A1 (2010).

71

Mochizuki M, Imaeda T, Aso K. Heterocyclic compound: WO 2011036885A1 (2011).

72

Aso K, Mochizuki M, Miura S, Imaeda T, Toyofuku M. Heterocyclic compound: WO 2011036889A1 (2011).

73

Kori M, Imaeda T, Nakamura S et al. Heterocyclic compound and use thereof: WO 2012020848A1 (2012).

74

Fukumoto S, Ujikawa O, Morimoto S et al. Sulfonamide derivative and use thereof: WO 2012137982A2 (2012).

75

Shaffer C L, Hurst R S, Scialis R J et al. Positive allosteric modulation of AMPA receptors from efficacy to toxicity: the interspecies exposure-response continuum of the novel potentiator PF-4778574. J. Pharmacol. Exp. Ther. 347, 212–224 (2013).

76

Patel N C, Schwarz J, Hou X J et al. Discovery and characterization of a novel dihydroisoxazole class of α‐amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiators. J. Med. Chem. 56, 9180–9191 (2013).

77

Jamieson C, Basten S, Campbell R A et al. A novel series of positive modulators of the AMPA receptor: discovery and

47

Details of the development status of CX1739. www.cortexpharm.com

48

Nations KR, Dogterom P, Bursi R et al. Examination of Org 26576, an AMPA receptor positive allosteric modulator, in patients diagnosed with major depressive disorder: an exploratory, randomized, double-blind, placebo-controlled trial. J. Psychopharmacol. 26(12), 1525–1539 (2012).

49

50

51

52

Adler LA, Kroon RA, Stein M, Shahid M, Tarazi FI. A translational approach to evaluate the efficacy and safety of the novel AMPA receptor positive allosteric modulator org 26576 in adult attention-deficit/hyperactivity disorder. Biol. Psychiatry 72(11), 971–977 (2012)49. Chapell AS. AMPA potentiator treatment of cognitive deficits in Alzheimer disease, Neurology 68(13), 1008 (2007) Trzepacz PT, Cummings J, Konechnik T et al. Mibampator (LY451395) randomized clinical trial for agitation/ aggression in Alzheimer’s disease. Int. Psychogeriatr. 25(5), 707–719 (2013). Evaluation of Single and Repeat Doses of GSK729327 in Healthy Volunteers, https://clinicaltrials.gov/ct2/show/ NCT00448890

53

Multiple Ascending Doses of PF-04958242 in Subjects With Stable Schizophrenia (MAD). https://clinicaltrials.gov/ct2/show/NCT02332798

54

Ward SE, Harries M, Aldegheri L et al. Discovery of N-[(2S)-5-(6-fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2yl]-2-propanesulfonamide, a novel clinical AMPA receptor positive modulator. J. Med. Chem. 53(15), 5801–5812 (2010).

55

O’donnell CJ. PF-4958242: a novel AMPA positive allosteric modulator (PAM) for the treatment of cognitive deficits associated with schizophrenia. 242nd ACS Natl Meet. Abst. MEDI 27 (2011).

56

Pirotte B, Francotte P, Goffin E, De Tullio P. AMPA receptor positive allosteric modulators: a patent review. Exp. Op. Ther. Patents 23(5), 615–628 (2013).

•

Thorough review of patents covering AMPA receptor positive allosteric modulators up to 2013.

57

Bradley DM, Chan WN, Thewlis KM, Ward SE. Compounds which potentiate AMPA receptor and uses thereof in medicine: WO 2008053031A1 (2008).

58

Bertheleme N, Bradley DM, Cardullo F et al. Compounds which potentiate AMPA receptor and uses thereof in medicine: WO 2008113795A1 (2008).



Review

489

Review Ward, Pennicott & Beswick structure based hit-to-lead studies Bioorg. Med. Chem. Lett. (20), 5753–5756 (2010). 78

79

Jamieson C, Basten S, Campbell R A et al. A novel series of positive modulators of the AMPA receptor: structure-based lead optimization Bioorg. Med. Chem. Lett. (20) 6072–6075 (2010). Timm D E, Benveniste M, Weeks AM et al. Structural and functional analysis of two new positive allosteric modulators of GluA2 desensitization and deactivation. Mol. Pharmacol. 80, 267–280 (2011).

92

Fliri AFJJ, Gallaschun RJ, O’donnell CJ, Schwarz JB, Segelstein BE. Heterocyclic sulfonamides, uses and pharmaceutical compositions thereof: WO 2010150192A1 (2010).

93

Estep KG, Fliri AFJ, O’donnell CJ. Sulfonamides and pharmaceutical compositions thereof: WO 2008120093A1 (2008).

94

Gillen KJ, Jamieson C, Maclean JKF, Moir EM, Rankovic Z. Pyrazolealkanamide substituted thiophenes as ampa potentiators: WO 2008003452A1 (2008).

80

Mueller R, Zhong S, Hampson A et al. Benzoxazinones as potent positive allosteric AMPA receptor modulators: Part I Bioorg. Med. Chem. Lett. (21), 3923–3926 (2011).

95

Gillespie J, Jamieson C, Maclean JKF, Moir EM, Rankovic Z. Indane derivatives as ampa receptor modulators: WO 2009147167A1 (2009).

81

Mueller R, Zhong S, Hampson A et al. Benzoxazinones as potent positive allosteric AMPA receptor modulators: Part 2 Bioorg. Med. Chem. Lett. (21), 3927–3930 (2011).

96

Gallagher MG, Jamieson C, Lyons AJ, Maclean JKF, Moir EM. Heterocyclic derivatives: WO 2009062930A1 (2009).

97

82

Mueller R, Rachwal S, Lee S et al. Benzotriazinone and benzopyrimidinone derivatives as potent positive allosteric AMPA receptor modulators Bioorg. Med. Chem. Lett. (21), 6170–6175 (2011).

Gillen KJ, Gillespie J, Jamieson C, Maclean JKF, Moir EM, Rankovic Z. Indane derivatives: WO 2010115952A1 (2010).

98

Mueller R, Rachwal S, Varney M A et al. Benzobistriazinones and related heterocyclic ring systems as potent, orally bioavailable positive allosteric AMPA receptor modulators Bioorg. Med. Chem. Lett. (21), 7455–7459 (2011).

Mueller R, Lee S, O’hare S, Rogers G, Rachwal S, Street L. Benzotriazinone derivatives as AMPA receptor enhancers and their preparation, pharmaceutical compositions and use in the treatment of diseases: WO2008085505A1 (2008).

99

Cordi A, Rogers G. 3-substituted-[1,2,3]-benzotriazinone compound for enhancing glutamatergic synaptic responses: WO 2008085506A1 (2008).

83

84

85

86

Bernard K, Danober L, Thomas JY et al. DRUG FOCUS: S 18986: a positive allosteric modulator of AMPA-type glutamate receptors pharmacological profile of a novel cognitive enhancer. CNS Neurosci. Ther. 16(5):e193–21 (2010). Norholm A-B, Francotte P, Olsen L et al. Synthesis, pharmacological and structural characterization, and thermodynamic aspects of GluA2-positive allosteric modulators with a 3,4-dihydro‐2H‐1,2,4-benzothiadiazine 1,1-dioxide scaffold. J. Med. Chem. 56, 8736–8745 (2013). Dintilhac G, Arslan D, Dilly S et al. New substituted aryl esters and aryl amides of 3,4-dihydro-2H-1,2,4benzothiadiazine 1,1-dioxides as positive allosteric modulators of AMPA receptors. Med. Chem. Commun., 2, 509–523 (2011).

87

Battisti U M, Ozwiak K, Cannazza G et al. 5-Arylbenzothiadiazine type compounds as positive allosteric modulators of AMPA/kainate receptors. ACS Med. Chem. Lett. 3(1), 25–29 (2012).

88

Cannazza G, Jozwiak K, Parenti C et al. A novel class of allosteric modulators of AMPA/Kainate receptors. Bioorg. Med, Chem. Lett. 19, 1254–1257 (2009).

89

Chen H, Wang C Z, Ding C et al. A combined bioinformatics and chemoinformatics approach for developing asymmetric bivalent AMPA receptor positive allosteric modulators as neuroprotective agents. Chem. Med. Chem. 8, 226–230 (2013).

90

Estep KG, Fliri AFJJG, O’donnell C, Patel NC, Schwarz JB, Xie L. Oxopiperidinyl and pyranyl sulfonamides as AMPA potentiators: WO 2010038167A1 (2010).

91

Estep KG, O’donnell CJ, Xie L. Tetrahydrofuranyl sulfonamides for use as AMPA modulators in the treatment of CNS disorders: WO 2010041162A1 (2010).

100 Mueller R, Street LJ, Rachwal S, Alisala K. Preparation of

substituted triazinone derivatives and analogs as glutamatergic synaptic response enhancers: WO2009038752A2 (2009). 101 Cordi A, Desos P, Lestage P, Danober L. Benzothiadiazepine

derivatives used as AMPA and NMDA receptor modulators: WO 2010106249A1 (2010). 102 Francotte P, De Tullio P, Pirotte B, Danober L, Lestage

P, Caignard D-H. New cycloalkylated benzothiadiazine derivatives, method for preparing them and pharmaceutical compositions containing them: WO 2010004139A1 (2010). 103 De Tullio P, Pirotte B, Botez L, Danober L, Lestage P. Novel

derivatives of cyclopropylated benzothiadiazines, method for preparing same and pharmaceutical compositions containing same: WO 2011083265A1 (2011). 104 Francotte P, De Tullio P, Pirotte B, Botez I, Danober L,

Lestage P. Thiochroman derivatives, method for preparing same and pharmaceutical compositions containing same: WO 2011083264A1. 105 Cordi A, Desos P, Lestage P, Laurence D.

Dihydrobenzoxathiazepine derivatives, preparation thereof, pharmaceutical compositions and use as ampa receptor modulators: WO 2012035216A1 (2012). 106 Battisti U, Cannazza G, Puja G et al. 1,2,4-Benzothiadiazine

dioxide derivatives as allosteric modulators of AMPA receptor and their preparation and use for treatment of mnemocognitive disorders: EP2457906A1 (2012). 107 Zhou, J, Chen Haijun, Johnson, K, Wang C. Bivalent AMPA

receptor positive allosteric modulators: WO 2013130501A1 (2013). 108 Gouaux JE, Song L, Xie Y, Landry D. Glur2 Receptor

Modulators: WO 2010087982A1 (2010). 109 Zapolsky ME, Zefirov NS, Palyulin VA et al.

4,4’-Biphenylamide derivatives having a pharmacological

490




activity, and medicaments based thereon: WO 2012138254A2 (2012).

112 Menniti F S, Lindsley C W, Conn P J et al. Allosteric

modulators for the treatment of schizophrenia: targeting glutamatergic networks. Curr. Top. Med. Chem. 13(1), 26–54 (2014).

110 Zapolsky ME, Zefirov NS, Palyulin VA, Lavrov MI.

Pharmacologically active alicyclic N,N’-substituted 3,7-diazabicyclo[3. 3. 1]nonane derivatives and drugs based thereon: WO 2012148308A1 (2012). 111 Grove S J A, Jamieson C, Maclean J F K, Morrow J A,

Rankovic Z. Positive allosteric modulators of the α-amino3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. J. Med. Chem. 53(20) 7271–7279 (2010). •

Review

•

Review of progress in identifying allosteric modulators of AMPA receptors, NMDA receptors, and metabotropic glutamate receptors as potetnial new treatments for Schizophrenia.Table 3. Chemotypes described in

the scientific literature 2008–2014 (cont.).

Short review of the status of medicinal chemisty research in the AMPA positivie allosteric modulator field up to 2010.



491

Are AMPA receptor positive allosteric modulators potential pharmacotherapeutics for addiction?

Drug treatment of schizophrenia. Overview of recent research.

Recent Advances in Biosensor Technology for Potential Applications - An Overview.

Role of stoichiometry in the dimer-stabilizing effect of AMPA receptor allosteric modulators.

Enhancing NMDA Receptor Function: Recent Progress on Allosteric Modulators.

Potassium channel modulators as possible treatment for pain: patent highlight.

Kainate Receptors.

Strategies for stem cell patent applications in the light of recent court cases.

Schizophrenia: overview and treatment options.

GPR119 Modulators for the Treatment of Diabetes, Obesity, and Related Diseases: Patent Highlight.

Sirtuin modulators: an updated patent review (2012 - 2014).

Allosteric modulators: an emerging concept in drug discovery.

Positive allosteric modulators of nicotinic acetylcholine receptor.

Allosteric modulators of human A2B adenosine receptor.

Allosteric modulators hit the TSH receptor.

The Nithsdale schizophrenia surveys. An overview.

Screening for AMPA receptor auxiliary subunit specific modulators.

Recent applications of chemosensitivity tests for colorectal cancer treatment.

Allosteric Modulators of the M4 Muscarinic Acetylcholine Receptor.

The 5-HT1A receptor: an overview of recent advances.

The adolescent brain: an overview of recent research.

Cognitive model and cognitive behavior therapy for schizophrenia: an overview.

PDK1 disruptors and modulators: a patent review.

Stimuli responsive ionogels for sensing applications-an overview.