Discovery and Lead Optimization of a Novel Series of CC Chemokine Receptor 1 (CCR1)-Selective Piperidine Antagonists via Parallel Synthesis

详细信息    查看全文

• 作者：Cullen L. Cavallaro ; Stephanie Briceno ; Jing Chen ; Mary Ellen Cvijic ; Paul Davies ; John Hynes ; Jr. ; Rui-Qin Liu ; Sandhya Mandlekar ; Anne V. Rose ; Andrew J. Tebben ; Katy Van Kirk ; Andrew Watson ; Hong Wu ; Guchen Yang ; Percy H. Carter
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 26, 2012
• 年：2012
• 卷：55
• 期：22
• 页码：9643-9653
• 全文大小：412K
• 年卷期：v.55,no.22(November 26, 2012)
• ISSN：1520-4804

文摘

A series of novel, potent CCR1 inhibitors was developed from a moderately active hit using an iterative parallel synthesis approach. The initial hit (composed of three subunits: an amine, a central amino acid, and an N-terminal cap) became the basis for a series of parallel chemical libraries designed to generate SAR data. Libraries were synthesized that explored each of the three subunits; the CCR1 binding data obtained revealed the following: (1) changes to the amine are not well tolerated; (2) small alkylamino acids are preferred in the center of the molecule; (3) substitutions at the N-terminus are generally well tolerated. These data were used to drive the optimization of the series, ultimately providing a lead with a CCR1 binding IC₅₀ of 28 nM (48). This lead demonstrates high selectivity for CCR1 over other CCR-family members, high microsomal stability, and good pharmacokinetics in mice.