Discovery of INCB3344, a potent, selective and orally bioavailable antagonist of human and murine CCR2

被引：34

作者：

Xue, Chu-Biao ^{[1
]}

Wang, Anlai ^{[1
]}

Meloni, David ^{[1
]}

Zhang, Ke ^{[1
]}

Kong, Ling ^{[1
]}

Feng, Hao ^{[1
]}

Glenn, Joseph ^{[1
]}

Huang, Taisheng ^{[1
]}

Zhang, Yingxin ^{[1
]}

Cao, Ganfeng ^{[1
]}

Anand, Rajan ^{[1
]}

Zheng, Changsheng ^{[1
]}

Xia, Michael ^{[1
]}

Han, Qi ^{[1
]}

Robinson, D. J. ^{[1
]}

Storace, Lou ^{[1
]}

Shao, Lixin ^{[1
]}

Li, Mei ^{[1
]}

Brodmerkel, Carrie M. ^{[1
]}

Covington, Maryanne ^{[1
]}

Scherle, Peggy ^{[1
]}

Diamond, Sharon ^{[1
]}

Yeleswaram, Swamy ^{[1
]}

Vaddi, Kris ^{[1
]}

Newton, Robert ^{[1
]}

Hollis, Greg ^{[1
]}

Friedman, Steven ^{[1
]}

Metcalf, Brian ^{[1
]}

机构：

[1] Incyte Corp, Wilmington, DE 19880 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 24期

关键词：

Human CCR2; Murine CCR2; Chemokine; Antagonist; MONOCYTE CHEMOATTRACTANT PROTEIN-1; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; CHEMOKINE RECEPTOR 2; RHEUMATOID-ARTHRITIS; MICE LACKING; PHARMACOLOGICAL CHARACTERIZATION; REDUCES ATHEROSCLEROSIS; MACROPHAGE RECRUITMENT; DEFICIENT MICE; DERIVATIVES;

D O I：

10.1016/j.bmcl.2010.10.020

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：7473 / 7478

页数：6

共 38 条

[1] Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2 [J].