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Synthesis and structure-activity relationships of indazole arylsulfonamides as allosteric CC-chemokine receptor 4 (CCR4) antagonists. 2013
Panayiotis A Procopiou, and
John W Barrett, and
Nicholas P Barton, and
Malcolm Begg, and
David Clapham, and
Royston C B Copley, and
Alison J Ford, and
Rebecca H Graves, and
David A Hall, and
Ashley P Hancock, and
Alan P Hill, and
Heather Hobbs, and
Simon T Hodgson, and
Coline Jumeaux, and
Yannick M L Lacroix, and
Afjal H Miah, and
Karen M L Morriss, and
Deborah Needham, and
Emma B Sheriff, and
Robert J Slack, and
Claire E Smith, and
Steven L Sollis, and
Hugo Staton
Department of Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom. pan.a.procopiou@gsk.com
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.
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