Synthesis and Structure鈥揂ctivity Relationships of Indazole Arylsulfonamides as Allosteric CC-Chemokine Receptor 4 (CCR4) Antagonists

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• 作者：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 ; Alan P. Hill ; Heather Hobbs ; Simon T. Hodgson ; 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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 14, 2013
• 年：2013
• 卷：56
• 期：5
• 页码：1946-1960
• 全文大小：644K
• 年卷期：v.56,no.5(March 14, 2013)
• ISSN：1520-4804

文摘

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 伪-amino-3-[(methylamino)acyl]鈥?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.