Discovery of 3-Piperidinyl-1-cyclopentanecarboxamide as a Novel Scaffold for Highly Potent CC Chemokine Receptor 2 Antagonists

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• 作者：Lihu Yang ; Gabor Butora ; Richard X. Jiao ; Alex Pasternak ; Changyou Zhou ; William H. Parsons ; Sander G. Mills ; Pasquale P. Vicario ; Julia M. Ayala ; Margaret A. Cascieri ; Malcolm MacCoss
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：May 31, 2007
• 年：2007
• 卷：50
• 期：11
• 页码：2609 - 2611
• 全文大小：53K
• 年卷期：v.50,no.11(May 31, 2007)
• ISSN：1520-4804

文摘

Introduction of ring restrictions to a linear aminobutyramideCC chemokine receptor 2 (CCR2) antagonist lead (2) led to thediscovery of a 1,3-disubstituted cyclopentane scaffold with enhancedhCCR2 receptor binding and antagonist activity. (1S,3R)-N-[3,5-Bis(trifluoromethyl)benzyl]-1-methyl-3-[(1R,3'R)-methyl-1'H-spiro[indene-1,4'-piperidin]-1'-yl]cyclopentanecarboxamide (16) had IC₅₀ of 1.3 nM(binding) and 0.45 nM (functional chemotaxis) against hCCR2. It alsoshowed activity against the mouse CCR2 receptor with an IC₅₀ of 130nM. Compound 16 is selective against other chemokine receptors,including CCR5 (~500-fold).