Novel, Orally Bioavailable -Aminoamide CC Chemokine Receptor 2 (CCR2) Antagonists

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• 作者：Alexander Pasternak ; Dominick Marino ; Pasquale P. Vicario ; Julia Marie Ayala ; Margaret A. Cascierri ; William Parsons ; Sander G. Mills ; Malcolm MacCoss ; Lihu Yang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：August 10, 2006
• 年：2006
• 卷：49
• 期：16
• 页码：4801 - 4804
• 全文大小：106K
• 年卷期：v.49,no.16(August 10, 2006)
• ISSN：1520-4804

文摘

Through modification of a screening hit we have discovereda structurally distinct new lead, (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-(4-fluorophenyl)-4-(4-phenylpiperidin-1-yl)butanamide (11), whichhas subsequently served as the departure point for an ongoing programtargeting CCR2 antagonists. Optimization of 11 leading to antagonists26 and 37 is described. Antagonist 26 was shown to have good oralbioavailability in rats. Antagonist 37 had a CCR2 IC₅₀ of 59 nM andexcellent potency in a functional assay measuring inhibition of MCP-1induced monocyte chemotaxis (IC₅₀ of 41 nM).