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Panayiotis A Procopiou,
John W Barrett,
Nicholas P Barton,
Malcolm Begg,
David Clapham,
Royston C B Copley,
Alison J Ford,
Rebecca H Graves,
David A Hall,
Ashley P Hancock, [......],
Coline Jumeaux,
Yannick M L Lacroix,
Afjal H Miah,
Karen M L Morriss, Deborah Needham,
Emma B Sheriff,
Robert J Slack,
Claire E Smith,
Steven L Sollis,
Hugo Staton
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ABSTRACT: A series of indazole arylsulfonamides were synthesized and examined as human CCR4 antagonists. Methoxy- or hydroxyl- containing groups were the more potent indazole C4 substituents. Only small groups were tolerated at C5, C6, or C7, with the C6 analogues being preferred. The most potent N3-substituent was 5-chlorothiophene-2-sulfonamide. N1 meta-substituted benzyl groups possessing an α-amino-3-[(methylamino)acyl]- group were the most potent N1-substituents. Strongly basic amino groups had low oral absorption in vivo. Less basic analogues, such as morpholines, had good oral absorption; however, they also had high clearance. The most potent compound with high absorption in two species was analogue 6 (GSK2239633A), which was selected for further development. Aryl sulfonamide antagonists bind to CCR4 at an intracellular allosteric site denoted site II. X-ray diffraction studies on two indazole sulfonamide fragments suggested the presence of an important intramolecular interaction in the active conformation.
Journal of Medicinal Chemistry 02/2013; · 4.80 Impact Factor
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ABSTRACT: Synthesis and preliminary SAR of the N1 substituent of a novel series of indazole sulfonamide chemokine receptor 4 (CCR4) antagonist is reported. Compound 7r was identified for further development.
Bioorganic & medicinal chemistry letters 03/2012; 22(8):2730-3. · 2.65 Impact Factor
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ABSTRACT: A series of novel, potent and selective human β(2) adrenoceptor agonists incorporating a urea moiety on the terminal right-hand side phenyl ring of (R)-salmeterol is presented. Urea 9j had long duration of action in vitro on guinea pig trachea, and also in vivo similar to that of salmeterol. It had lower oral absorption and bioavailability than salmeterol in both rat and dog. It had a turnover ratio similar to salmeterol, with no evidence for formation of any aniline metabolites in human liver microsomes and hepatocytes. However no crystalline salts suitable for inhaled delivery were identified.
Bioorganic & medicinal chemistry 08/2011; 19(20):6026-32. · 2.82 Impact Factor
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Keith Biggadike,
Mohamed Boudjelal,
Margaret Clackers,
Diane M Coe,
Derek A Demaine,
George W Hardy,
Davina Humphreys,
Graham G A Inglis,
Michael J Johnston,
Haydn T Jones,
David House,
Richard Loiseau, Deborah Needham,
Philip A Skone,
Iain Uings,
Gemma Veitch,
Gordon G Weingarten,
Iain M McLay,
Simon J F Macdonald
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ABSTRACT: The synthesis and biological activity of tetrahydronaphthalene derivatives coupled to various heterocycles are described. These compounds are potent glucocorticoid receptor agonists with efficacy selectivity in an NFkappaB glucocorticoid receptor (GR) agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). Quinolones, indoles, and C- and N-linked quinolines are some of the heterocycles that provide efficacy selectivity. For example, the isoquinoline 49D1E2 has NFkappaB agonism with pIC50 of 8.66 (89%) and reduced efficacy in MMTV agonism (6%), and the quinoline 55D1E1 has NFkappaB agonism with pIC50 of 9.30 (101%) and reduced efficacy in MMTV agonism with pEC50 of 8.02 (47%). A description of how a compound from each class is modeled in the active site of the receptor is given.
Journal of Medicinal Chemistry 01/2008; 50(26):6519-34. · 5.25 Impact Factor
