Isoindolone Formation via Intramolecular Diels–Alder Reaction

Ball, Matthew; Boyd, Alistair; Churchill, Gwydion H.; Cuthbert, Murray W.; Drew, Mark D.; Fielding, Mark R.; Ford, G. H.; Frodsham, Lianne; Golden, Michael; Leslie, Kevin; Lyons, Sarah E.; McKeever‐Abbas, Ben; Stark, Andrew; Tomlin, Paula; Gottschling, Stephen E.; Hajar, Abraham; Ji-Long, Jiang; Lo, Josephine; Suchozak, Bob

doi:10.1021/op300002f

Cited by 28 publications

(9 citation statements)

References 12 publications

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“…285 There is also a publication providing details on the process chemistry optimization of the synthesis of AZD8529 ( 13 ) that describes the development of an intramolecular Diels-Alder reaction for the rapid synthesis of the key indolinone intermediate 57 . 286 Even though AZD8529 ( 13 ) was active in seven preclinical antipsychotic and two anxiolytic models, in a phase II study in patients with symptomatic schizophrenia, the compound failed to distinguish from placebo. It should be noted that this trial was conducted at a single dose and lacked a method for directly measuring target engagement (e.g., PET).…”

Section: 2 Allosteric Modulators Of the Mglu2 And Mglu3 Receptorsmentioning

confidence: 99%

Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors

et al. 2016

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Allosteric modulation of GPCRs has initiated a new era of basic and translational discovery, filled with therapeutic promise yet fraught with caveats. Allosteric ligands stabilize unique conformations of the GPCR that afford fundamentally new receptors, capable of novel pharmacology, unprecedented subtype selectivity, and unique signal bias. This review provides a comprehensive overview of the basics of GPCR allosteric pharmacology, medicinal chemistry, drug metabolism, and validated approaches to address each of the major challenges and caveats. Then, the review narrows focus to highlight recent advances in the discovery of allosteric ligands for metabotropic glutamate receptor subtypes 1–5 and 7 (mGlu 1–57) highlighting key concepts (“molecular switches”, signal bias, heterodimers) and practical solutions to enable the development of tool compounds and clinical candidates. The review closes with a section on late-breaking new advances with allosteric ligands for other GPCRs and emerging data for endogenous allosteric modulators.

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Section: 2 Allosteric Modulators Of the Mglu2 And Mglu3 Receptorsmentioning

confidence: 99%

Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors

et al. 2016

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“…Importantly, two mGlu 2 PAMs have reached clinical trials so far. Development of AZD8529 (described in patent WO2008150233, Ball et al , ) from AstraZeneca was discontinued after a phase 2a study in schizophrenic patients due to a lack of efficacy (Cook et al , ). JNJ‐40411813 (also known as ADX71149) from Janssen Pharmaceuticals and Addex Therapeutics failed to meet the criterion for efficacy signal in patients with major depressive disorder with significant anxiety symptoms.…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanism of positive allosteric modulation of the metabotropic glutamate receptor 2 by JNJ‐46281222

Doornbos

Pérez‐Benito

Tresadern³

et al. 2016

British J Pharmacology

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BACKGROUND AND PURPOSEAllosteric modulation of the mGlu 2 receptor is a potential strategy for treatment of various neurological and psychiatric disorders. Here, we describe the in vitro characterization of the mGlu 2 positive allosteric modulator (PAM) JNJ-46281222 and its radiolabelled counterpart [3 H]-JNJ-46281222. Using this novel tool, we also describe the allosteric effect of orthosteric glutamate binding and the presence of a bound G protein on PAM binding and use computational approaches to further investigate the binding mode. EXPERIMENTAL APPROACHWe have used radioligand binding studies, functional assays, site-directed mutagenesis, homology modelling and molecular dynamics to study the binding of JNJ-46281222. KEY RESULTSJNJ-46281222 is an mGlu 2 -selective, highly potent PAM with nanomolar affinity (K D = 1.7 nM). Binding of CONCLUSION AND IMPLICATIONSOur results obtained with JNJ-46281222 in unlabelled and tritiated form further contribute to our understanding of mGlu 2 allosteric modulation. The computational simulations and mutagenesis provide a plausible binding mode with indications of how the ligand permits allosteric activation. This study is therefore of interest for mGlu 2 and class C receptor drug discovery.

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“…3, 140.2, 137.1, 134.9, 134.0, 129.4, 98.6, 26.0, 19.5. 4-Fluoro-2,6-dimethylbenzoic Acid (3e): 37.8 mg, 75% yield, white solid; 1 H NMR (500 MHz, CDCl 3 ) δ 6.78 (d, J = 9.3 Hz, 2H), 2.44 (s, 6H); 13 : 37 mg, 67% yield, white solid; 1 H NMR (500 MHz, CDCl 3 ) δ 7.08 (s, 2H), 2.42 (s, 6H); 13 C{ 1 H} NMR (126 MHz, CDCl 3 ) δ 174. 1, 137.9, 135.6, 127.9, 127.8, 20. 4-Bromo-2,6-dimethylbenzoic Acid (3g): 16 30.8 mg, 45% yield, white solid; 1 H NMR (500 MHz, CDCl 3 ) δ 7.25 (s, 2H), 2.41 (s, 6H); 13 C{ 1 H} NMR (126 MHz, CDCl 3 ) δ 173. 9,138.0,131.1,130.8,124.1,20.1.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%