| Literature DB >> 21036044 |
Chu-Biao Xue1, Anlai Wang, David Meloni, Ke Zhang, Ling Kong, Hao Feng, Joseph Glenn, Taisheng Huang, Yingxin Zhang, Ganfeng Cao, Rajan Anand, Changsheng Zheng, Michael Xia, Qi Han, D J Robinson, Lou Storace, Lixin Shao, Mei Li, Carrie M Brodmerkel, Maryanne Covington, Peggy Scherle, Sharon Diamond, Swamy Yeleswaram, Kris Vaddi, Robert Newton, Greg Hollis, Steven Friedman, Brian Metcalf.
Abstract
Rational design based on a pharmacophore of CCR2 antagonists reported in the literature identified lead compound 9a with potent inhibitory activity against human CCR2 (hCCR2) but moderate activity against murine CCR2 (mCCR2). Modification on 9a led to the discovery of a potent CCR2 antagonist 21 (INCB3344) with IC(50) values of 5.1 nM (hCCR2) and 9.5 nM (mCCR2) in binding antagonism and 3.8 nM (hCCR2) and 7.8 nM (mCCR2) in antagonism of chemotaxis activity. INCB3344 exhibited >100-fold selectivity over other homologous chemokine receptors, a free fraction of 24% in human serum and 15% in mouse serum, and an oral bioavailability of 47% in mice, suitable as a tool compound for target validation in rodent models.Entities:
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Year: 2010 PMID： 21036044 DOI： 10.1016/j.bmcl.2010.10.020
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823