4-Amino-2-alkyl-butyramides as small molecule CCR2 antagonists with favorable pharmacokinetic properties

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• 作者：Gabor Butora ; Gregori J. Morriello ; Shankaran Kothandaraman ; Deodialsingh Guiadeen ; Alexander Pasternak ; William H. Parsons ; Malcolm MacCoss ; Pasquale P. Vicario ; Margaret A. Cascieri and Lihu Yang
• 关键词：CCR2 ; Chemokines ; Antagonists
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2006
• 出版时间：15 September 2006
• 年：2006
• 卷：16
• 期：18
• 页码：4715-4722
• 全文大小：185 K

文摘

A systematic examination of the central aromatic portion of the lead (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-(4-fluorophenyl)-4-(1′H-spiro[indene-1,4′-piperidin]-1′-yl)butanamide (9) led to the discovery of a novel class of CCR2 receptor antagonists, which carry small alicyclic groups such as cyclopropyl, cylobutyl, or cyclopropylmethyl attached at C₂ of the carbon backbone. The most potent compound discovered, namely (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-cyclopropyl-4-[(1R,3′R)-3′-methyl-1′H-spiro[indene-1,4′-piperidin]-1′-yl]butanamide (29), showed very high binding affinity (IC₅₀ = 4 nM, human monocyte) and excellent selectivity toward other related chemokine receptors. The excellent pharmacokinetic profile of this new lead compound allows for extensive in vivo evaluation.