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Paul A Stupple, David V Batchelor,
Martin Corless,
Patrick K Dorr,
David Ellis,
David R Fenwick,
Sébastien R G Galan,
Rhys M Jones,
Helen J Mason,
Donald S Middleton,
Manos Perros,
Francesca Perruccio,
Michelle Y Platts,
David C Pryde,
Deborah Rodrigues,
Nicholas N Smith,
Peter T Stephenson,
Robert Webster,
Mike Westby,
Anthony Wood
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ABSTRACT: Preventing entry of HIV into human host cells has emerged as an attractive approach to controlling viral replication. Maraviroc 1 is an approved antagonist of the human CCR5 receptor which prevents the entry of HIV. Herein, we report the design and discovery of a series of imidazopiperidine CCR5 antagonists which retain the attractive antiviral profile and window over hERG activity of maraviroc 1, combined with improved absorption profiles in rat and dog. Furthermore, this series of compounds has been shown to retain activity against a laboratory generated maraviroc-resistant HIV-1 strain, which indicates an alternative resistance profile to that of maraviroc 1. Compound 41f (PF-232798) was selected as a clinical candidate from the imidazopiperidine series and is currently in phase II clinical trials.
Journal of Medicinal Chemistry 12/2010; 54(1):67-77. · 4.80 Impact Factor
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Mark D Andrews,
Martin P Green,
Charlotte M N Allerton, David V Batchelor,
Julian Blagg,
Alan D Brown,
David W Gordon,
Gordon McMurray,
Daniel J Millns,
Carly L Nichols,
Lesa Watson
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ABSTRACT: This Letter reports the design and synthesis of several novel series of piperazinyl pyrimidinones as 5-HT(2C) agonists. Several of the compounds presented exhibit good in vitro potency and selectivity over the closely related 5-HT(2A) and 5-HT(2B) receptors. Compound 11 was active in in vivo models of stress urinary incontinence.
Bioorganic & medicinal chemistry letters 09/2009; 19(18):5346-50. · 2.65 Impact Factor
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Simon J Mantell,
Peter T Stephenson,
Sandra M Monaghan,
Graham N Maw,
Michael A Trevethick,
Michael Yeadon,
Don K Walker,
Matthew D Selby, David V Batchelor,
Stuart Rozze,
Helene Chavaroche,
Arnaud Lemaitre,
Karen N Wright,
Lynsey Whitlock,
Emilio F Stuart,
Patricia A Wright,
Fiona Macintyre
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ABSTRACT: COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. The pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists is described leading through to human pharmacokinetic data for a clinical candidate.
Bioorganic & medicinal chemistry letters 06/2009; 19(15):4471-5. · 2.65 Impact Factor
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Simon J Mantell,
Peter T Stephenson,
Sandra M Monaghan,
Graham N Maw,
Michael A Trevethick,
Michael Yeadon,
Ruth F Keir,
Don K Walker,
Rhys M Jones,
Matthew D Selby, David V Batchelor,
Stuart Rozze,
Helene Chavaroche,
Tim J Hobson,
Peter G Dodd,
Arnaud Lemaitre,
Karen N Wright,
Emilio F Stuart
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ABSTRACT: COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. A strategy of minimizing side-effect liability by maximizing systemic clearance was followed and pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists described. A sevenfold improvement in potency and 150-fold reduction in side-effect liability over the lead compound CGS-21680, were obtained.
Bioorganic & medicinal chemistry letters 03/2008; 18(4):1284-7. · 2.65 Impact Factor
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ABSTRACT: The title compounds are prepared from S-methylisothioureas and acyl hydrazides in moderate to good yields. The reaction is characterized by relatively mild conditions and very broad functional group tolerance.
Synlett 01/2008; · 2.71 Impact Factor
