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ABSTRACT: Optimisation of the potency of a bicyclic CRF antagonist whilst retaining metabolic stability is described. A core change and incorporation of metabolically stable lipophilic groups resulted in a further potency gain without increasing metabolic liability. Pharmacological investigation of binding kinetics led to the identification of compound 25, a sub-nanomolar CRF-1 antagonist with slow dissociation kinetics and an encouraging pharmacokinetic profile.
Bioorganic & medicinal chemistry letters 08/2011; 21(20):6108-11. · 2.65 Impact Factor
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Mark D Andrews,
Paul V Fish,
Julian Blagg,
Tiffini K Brabham,
Paul E Brennan,
Alison Bridgeland, Alan D Brown,
Peter J Bungay,
Kelly M Conlon,
Nicholas J Edmunds, [......],
Alan S Jessiman,
Karin McIntosh,
Gordon McMurray,
Carly L Nichols,
James A Root,
R Ian Storer,
Michael R Sutton,
Robin V Ward,
Dominique Westbrook,
Gavin A Whitlock
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ABSTRACT: New pyrimido[4,5-d]azepines 7 are disclosed as potent 5-HT(2C) receptor agonists. A preferred example, 7b had minimal activation at either the 5-HT(2A) or 5-HT(2B) receptors combined with robust efficacy in a preclinical canine model of stress urinary incontinence (SUI) and attractive pharmacokinetic and safety properties. Based on this profile, 7b (PF-3246799) was identified as a candidate for clinical development for the treatment of SUI. In addition, it proved to be critical to build an understanding of the translation between recombinant cell-based systems, native tissue preparations and in vivo preclinical models. This was a significant undertaking and proved to be crucial in compound selection.
Bioorganic & medicinal chemistry letters 12/2010; 21(9):2715-20. · 2.65 Impact Factor
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Paul A Glossop,
Charlotte A L Lane,
David A Price,
Mark E Bunnage,
Russell A Lewthwaite,
Kim James, Alan D Brown,
Michael Yeadon,
Christelle Perros-Huguet,
Michael A Trevethick,
Nicholas P Clarke,
Robert Webster,
Rhys M Jones,
Jane L Burrows,
Neil Feeder,
Stefan C J Taylor,
Fiona J Spence
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ABSTRACT: A novel series of potent and selective sulfonamide derived β(2)-adrenoreceptor agonists are described that exhibit potential as inhaled ultra-long-acting bronchodilators for the treatment of asthma and chronic obstructive pulmonary disease. Analogues from this series mediate very long-lasting smooth muscle relaxation in guinea pig tracheal strips. The sulfonamide agonist headgroup confers high levels of intrinsic crystallinity that could relate to the acidic sulfonamide motif supporting a zwitterionic form in the solid state. Optimization of pharmacokinetic properties was achieved through targeted introduction of a phenolic moiety to support rapid phase II clearance, thereby minimizing systemic exposure following inhalation and reducing systemically mediated adverse events. Compound 38 (PF-610355) is identified as a clinical candidate from this series, with in vivo duration of action studies confirming its potential for once-daily use in humans. Compound 38 is currently in advanced phase II clinical studies.
Journal of Medicinal Chemistry 09/2010; 53(18):6640-52. · 4.80 Impact Factor
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Paul A. Glossop,
Charlotte A. L. Lane,
David A. Price,
Mark E. Bunnage,
Russell A. Lewthwaite,
Kim James, Alan D. Brown,
Michael Yeadon,
Christelle Perros-Huguet,
Michael A. Trevethick,
Nicholas P. Clarke,
Robert Webster,
Rhys M. Jones,
Jane L. Burrows,
Neil Feeder,
Stefan C. J. Taylor,
Fiona J. Spence
[show abstract]
[hide abstract]
ABSTRACT: A novel series of potent and selective sulfonamide derived β2-adrenoreceptor agonists are described that exhibit potential as inhaled ultra-long-acting bronchodilators for the treatment of asthma and chronic obstructive pulmonary disease. Analogues from this series mediate very long-lasting smooth muscle relaxation in guinea pig tracheal strips. The sulfonamide agonist headgroup confers high levels of intrinsic crystallinity that could relate to the acidic sulfonamide motif supporting a zwitterionic form in the solid state. Optimization of pharmacokinetic properties was achieved through targeted introduction of a phenolic moiety to support rapid phase II clearance, thereby minimizing systemic exposure following inhalation and reducing systemically mediated adverse events. Compound 38 (PF-610355) is identified as a clinical candidate from this series, with in vivo duration of action studies confirming its potential for once-daily use in humans. Compound 38 is currently in advanced phase II clinical studies.
08/2010;
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Mark I Lansdell,
David Hepworth,
Andrew Calabrese, Alan D Brown,
Julian Blagg,
Denise J Burring,
Peter Wilson,
David Fradet,
T Bruce Brown,
Faye Quinton, [......],
Mark Lewis,
Hugh Verrier,
Val Gillon,
Neil Feeder,
Anne Heatherington,
Stefan Sultana,
Scott Haughie,
Steven W Martin,
Maria Sudworth,
Sarah Tweedy
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ABSTRACT: The relevance of the melanocortin system to sexual activity is well established, and nonselective peptide agonists of the melanocortin receptors have shown evidence of efficacy in human sexual dysfunction. The role of the MC4 receptor subtype has received particular scrutiny, but the sufficiency of its selective activation in potentiating sexual response has remained uncertain owing to conflicting data from studies in preclinical species. We describe here the discovery of a novel series of small-molecule MC4 receptor agonists derived from library hit 2. The addition of methyl substituents at C3 and C5 of the 4-phenylpiperidin-4-ol ring was found to be markedly potency-enhancing, enabling the combination of low nanomolar potencies with full rule-of-five compliance. In general, the series shows only micromolar activity at other melanocortin receptors. Our preferred compound 40a provided significant systemic exposure in humans on both sublingual and oral administration and was safe and well tolerated up to the maximum tested dose. In a pilot clinical study of male erectile dysfunction, the highest dose of 40a tested (200 mg) provided a similar level of efficacy to sildenafil.
Journal of Medicinal Chemistry 03/2010; 53(8):3183-97. · 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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ABSTRACT: Balancing potency and metabolic stability in a target which favours lipophilic ligands is a considerable challenge. Here we describe two strategies employed to achieve this balance in a series of pyrazolopyrimidine CRF antagonists: moderation of lipophilicity, and incorporation of a metabolically stable lipophilic group.
Bioorganic & medicinal chemistry letters 09/2009; 19(21):6144-7. · 2.65 Impact Factor
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ABSTRACT: New 7-sulfonamido-3-benzazepines 3 are disclosed as 5-HT(2C) receptor agonists. Appropriate substitution of the amino group (R(1)R(2)N-) gave compounds that were potent 5-HT(2C) agonists with minimal activation of the 5-HT(2A) and 5-HT(2B) receptors. Furthermore, representative examples had excellent in vitro ADME properties and good selectivity over ion channel activity.
Bioorganic & medicinal chemistry letters 05/2009; 19(7):1871-5. · 2.65 Impact Factor
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ABSTRACT: This review will detail the medicinal chemistry involved in the design, synthesis and discovery of
selective serotonin, noradrenaline reuptake inhibitors and dual serotonin/noradrenaline reuptake inhibitors.
In particular, this review will focus exclusively on series and compounds which have been disclosed within
the medicinal chemistry literature between January 2000 and June 2008. Background information on previously
disclosed clinical agents, such as atomoxetine, milnacipran and reboxetine, is included for comparison purposes
with more recently disclosed agents.
12/2008: pages 53-94;
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Synthetic Communications 08/2008; 38(16):2787-2798. · 1.06 Impact Factor
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Alan D Brown,
Mark E Bunnage,
Paul A Glossop,
Kim James,
Rhys Jones,
Charlotte A L Lane,
Russell A Lewthwaite,
Simon Mantell,
Christelle Perros-Huguet,
David A Price,
Mike Trevethick,
Rob Webster
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ABSTRACT: The design and profile of a series of adamantyl-containing long acting beta(2)-adrenoreceptor agonists are described. An optimal pharmacokinetic profile of low oral bioavailability was combined with a strong pharmacology profile when assessed using a guinea pig trachea tissue model. A focus was then placed on developing a robust synthetic route to ensure rapid delivery of material for clinical trials.
Bioorganic & medicinal chemistry letters 03/2008; 18(4):1280-3. · 2.65 Impact Factor
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Alan D Brown,
Mark E Bunnage,
Paul A Glossop,
Mark Holbrook,
Rhys D Jones,
Charlotte A L Lane,
Russell A Lewthwaite,
Simon Mantell,
Christelle Perros-Huguet,
David A Price,
Rob Webster
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ABSTRACT: The design and profile of a series of indole containing long acting beta(2)-adrenoceptor agonists is described. Evaluation of these analogues using an in vitro guinea pig trachea tissue model demonstrates that analogues within this series have salmeterol-like duration of action with potential for long duration of action in humans.
Bioorganic & Medicinal Chemistry Letters 12/2007; 17(22):6188-91. · 2.55 Impact Factor
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ABSTRACT: Dysfunction of female sexual desire, arousal, or orgasm affects approximately 30% of women. Early attempts to treat female sexual dysfunction arose out of programs developed for male erectile dysfunction and have proven largely unsuccessful. A new wave of targets is now being pursued; many of these targets are postulated to modulate central pathways. Classical neurotransmitter systems, such as dopamine and serotonin, as well as the neuropeptide melanocortin, are receiving the most attention. Early clinical data look promising; however, clinical trial methodology in female sexual dysfunction is not well developed and only further testing will determine whether these treatments meet regulatory hurdles and satisfy patient need.
Drug Discovery Today 10/2007; 12(17-18):757-66. · 6.83 Impact Factor
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Alan D Brown,
Mark E Bunnage,
Paul A Glossop,
Kim James,
Rhys Jones,
Charlotte A L Lane,
Russell A Lewthwaite,
Simon Mantell,
Christelle Perros-Huguet,
David A Price,
Mike Trevethick,
Rob Webster
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ABSTRACT: The design and profile of a series of saligenin containing long acting beta(2)-adrenoreceptor agonists is described. Evaluation of these analogues using a guinea-pig tissue model demonstrates that analogues within this series have significantly longer durations of action than salmeterol and have the potential for a once daily profile in human.
Bioorganic & Medicinal Chemistry Letters 08/2007; 17(14):4012-5. · 2.55 Impact Factor
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ABSTRACT: The synthesis and structure-activity relationships of a novel series of piperazine derivatives as dual inhibitors of serotonin and noradrenaline reuptake is described. Two compounds possessed comparable in vitro profiles to the dual reuptake inhibitor duloxetine.
Bioorganic & Medicinal Chemistry Letters 09/2006; 16(16):4345-8. · 2.55 Impact Factor
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John C Danilewicz,
Stuart M Abel, Alan D Brown,
Paul V Fish,
Edward Hawkeswood,
Stephen J Holland,
Keith James,
Andrew B McElroy,
John Overington,
Michael J Powling,
David J Rance
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ABSTRACT: Potent and selective inhibitors of thrombin were sought based on the (R)-Phe-Pro-Arg sequence. The objective was to generate similar binding interactions to those achieved by potent competitive inhibitors of the argatroban type, so eliminating the need for covalent interaction with the catalytic serine function, as utilized by aldehyde and boronic acid type inhibitors. Improving the S(1) subsite interaction by substitution of arginine with a 4-alkoxybenzamidine residue provided potent lead 2 (K(i) = 0.37 nM). Though an amide bond, which H-bonds to the active site, is lost, modeling indicated that a new H-bond is generated between the alkoxy oxygen atom and the catalytic Ser-195 hydroxyl group. Substitution of the benzamidine system by 1-amidinopiperidine then gave compound 4, which provided a further gain in selectivity over trypsin. However, previous work had shown that these compounds were likely to be too lipophilic (Log D +0.4 and +0.2, respectively) and to suffer rapid hepatic extraction, presumably via biliary elimination. Accordingly, both proved short-acting when administered intravenously to rats and showed poor activity when given intraduodenally. The aim was then to reduce lipophilicity below a log D of -1.2, which in a previously reported series had been effective in preventing rapid clearance. It was anticipated that compounds of this type would rely on the cation selective paracellular route of absorption from the gastrointestinal tract. Potent polar analogues with selectivity >1000 over trypsin were obtained. The best in vivo activity was shown by compound 12. However, in the final analysis, its oral bioavilability proved poor, relative to analogues with similar physicochemical properties derived from argatroban, consistent with the hypothesis that molecular shape is an additional important determinant of paracellular absorption.
Journal of Medicinal Chemistry 07/2002; 45(12):2432-53. · 5.25 Impact Factor
