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Dive into the research topics where Gerwyn Bish is active.

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Featured researches published by Gerwyn Bish.


Journal of Medicinal Chemistry | 2012

Identification of a chemical probe for bromo and extra C-terminal bromodomain inhibition through optimization of a fragment-derived hit.

Paul V. Fish; Panagis Filippakopoulos; Gerwyn Bish; Paul E. Brennan; Mark Edward Bunnage; Andrew Simon Cook; Oleg Federov; Brian S. Gerstenberger; Hannah M. Jones; Stefan Knapp; Brian D. Marsden; Karl H. Nocka; Dafydd R. Owen; Martin Philpott; Sarah Picaud; Michael J. Primiano; Michael Ralph; Nunzio Sciammetta; John David Trzupek

The posttranslational modification of chromatin through acetylation at selected histone lysine residues is governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The significance of this subset of the epigenetic code is interrogated and interpreted by an acetyllysine-specific protein–protein interaction with bromodomain reader modules. Selective inhibition of the bromo and extra C-terminal domain (BET) family of bromodomains with a small molecule is feasible, and this may represent an opportunity for disease intervention through the recently disclosed antiproliferative and anti-inflammatory properties of such inhibitors. Herein, we describe the discovery and structure–activity relationship (SAR) of a novel, small-molecule chemical probe for BET family inhibition that was identified through the application of structure-based fragment assessment and optimization techniques. This has yielded a potent, selective compound with cell-based activity (PFI-1) that may further add to the understanding of BET family function within the bromodomains.


Bioorganic & Medicinal Chemistry Letters | 2011

Design and optimisation of orally active TLR7 agonists for the treatment of hepatitis C virus infection.

Thien-Duc Tran; David C. Pryde; Peter Jones; Fiona M. Adam; Neil Benson; Gerwyn Bish; Frederick Calo; Guiseppe Ciaramella; Rachel Dixon; Jonathan Duckworth; David Nathan Abraham Fox; Duncan A. Hay; James R. Hitchin; Nigel Horscroft; Martin Howard; Iain Gardner; Hannah M. Jones; Carl Laxton; Tanya Parkinson; Gemma C. Parsons; Katie J. W. Proctor; Mya C. Smith; Nick N. Smith; Amy Thomas

The synthesis and structure-activity relationships of a series of novel interferon inducers are described. Pharmacokinetic studies and efficacy assessment of a series of 8-oxo-3-deazapurine analogues led to the identification of compound 33, a potent and selective agonist of the TLR7 receptor with an excellent in vivo efficacy profile in a mouse model.


Bioorganic & Medicinal Chemistry Letters | 2011

Discovery of a highly potent series of TLR7 agonists

Peter Jones; David C. Pryde; Thien-Duc Tran; Fiona M. Adam; Gerwyn Bish; Frederick Calo; Guiseppe Ciaramella; Rachel Dixon; Jonathan Duckworth; David Nathan Abraham Fox; Duncan A. Hay; James R. Hitchin; Nigel Horscroft; Martin Howard; Carl Laxton; Tanya Parkinson; Gemma C. Parsons; Katie J. W. Proctor; Mya C. Smith; Nick N. Smith; Amy Thomas

The discovery of a series of highly potent and novel TLR7 agonist interferon inducers is described. Structure-activity relationships are presented, along with pharmacokinetic studies of a lead molecule from this series of N9-pyridylmethyl-8-oxo-3-deazapurine analogues. A rationale for the very high potency observed is offered. An investigation of the clearance mechanism of this class of compounds in rat was carried out, resulting in aldehyde oxidase mediated oxidation being identified as a key component of the high clearance observed. A possible solution to this problem is discussed.


MedChemComm | 2011

The discovery of a novel prototype small molecule TLR7 agonist for the treatment of hepatitis C virus infection

David C. Pryde; Thien-Duc Tran; Peter Jones; Gemma C. Parsons; Gerwyn Bish; Fiona M. Adam; Mya C. Smith; Donald Stuart Middleton; Nick N. Smith; Frederick Calo; Duncan Hay; Michael Paradowski; Katie J. W. Proctor; Tanya Parkinson; Carl Laxton; David Nathan Abraham Fox; Nigel Horscroft; Giuseppe Ciaramella; Hannah M. Jones; Jonathan Duckworth; Neil Benson; Anthony Harrison; Rob Webster

A series of heterocycle analogues of an adenine template were explored for TLR7 agonist potency and pharmacokinetics. One compound was identified with an excellent pharmacokinetic, in vitro potency and in vivo interferon induction profile in a mouse model, and was selected for further pre-clinical evaluation as a potential treatment for hepatitis C viral infection.


Bioorganic & Medicinal Chemistry Letters | 2010

Second generation N-(1,2-diphenylethyl)piperazines as dual serotonin and noradrenaline reuptake inhibitors: Improving metabolic stability and reducing ion channel activity

M. Jonathan Fray; Paul V. Fish; Gillian A. Allan; Gerwyn Bish; Nick Clarke; Rachel Eccles; Anthony Harrison; Jean-Loic Le Net; Stephen Charles Phillips; Nicola Regan; Cécile Sobry; Alan Stobie; Florian Wakenhut; Dominique Westbrook; Simon Lempriere Westbrook; Gavin A. Whitlock

New N-(1,2-diphenylethyl)piperazines 6 are disclosed as dual serotonin and noradrenaline reuptake inhibitors (SNRI) which may have potential in treating stress urinary incontinence (SUI). In this Letter, we present new data for SNRI PF-526014 (4) including performance in a canine in vivo model of SUI, cardiovascular assessment, pharmacokinetics in dog and determination of the primary routes of metabolism in vitro. Starting from 4, detailed structure activity relationships established that potent dual SNRIs could be achieved by appropriate substitution of the phenyl rings (6: R; R(1)) combined with a preferred stereochemistry. From this set of compounds, piperazine (-)-6a was identified as a potent and selective dual SNRI with improved metabolic stability and reduced ion channel activity when compared to 4. Based on this profile, (-)-6a was selected for further evaluation in a preclinical model of SUI.


Bioorganic & Medicinal Chemistry Letters | 2006

N-(1,2-Diphenylethyl)piperazines: A new class of dual serotonin/noradrenaline reuptake inhibitor

M. Jonathan Fray; Gerwyn Bish; Alan Daniel Brown; Paul V. Fish; Alan Stobie; Florian Wakenhut; Gavin A. Whitlock


Bioorganic & Medicinal Chemistry Letters | 2006

Structure-activity relationships of N-substituted piperazine amine reuptake inhibitors

M. Jonathan Fray; Gerwyn Bish; Paul V. Fish; Alan Stobie; Florian Wakenhut; Gavin A. Whitlock


Tetrahedron Letters | 2009

Enantioselective synthesis of (R)-and (S)-N-Boc-morpholine-2-carboxylic acids by enzyme-catalyzed kinetic resolution : application to the synthesis of reboxetine analogs

Paul V. Fish; Malcolm MacKenny; Gerwyn Bish; Timothy Buxton; Russell Cave; David Drouard; D.W.T. Hoople; Alan S. Jessiman; Duncan Charles Miller; Christelle Pasquinet; Bhairavi Patel; Keith Reeves; Thomas Ryckmans; Melanie Skerten; Florian Wakenhut


Archive | 2005

Piperazine derivatives which exhibit activity as serotonin and noradrenaline re-uptake inhibitors

Gerwyn Bish; Alan Daniel Brown; Paul V. Fish; Michael Jonathan Fray; Alan Stobie; Florian Wakenhut; Gavin A. Whitlock


Organic Process Research & Development | 2011

Development of a Practical Synthesis of Toll-like Receptor Agonist PF-4171455: 4-Amino-1-benzyl-6-trifluoromethyl-1,3-dihydroimidazo [4,5-c] pyridin-2-one

Fiona M. Adam; Gerwyn Bish; Frederick Calo; Christopher L. Carr; Nieves Castro; Duncan Hay; Paul Hodgson; Peter G. Jones; Craig J. Knight; Michael Paradowski; Gemma C. Parsons; Katie J. W. Proctor; David C. Pryde; Filippo Rota; Mya C. Smith; Nicholas D. Smith; Thien-Duc Tran; James R. Hitchin; Rachel Dixon

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