Discovery of INCB3344, a potent, selective and orally bioavailable antagonist of human and murine CCR2
| Autor: | Taisheng Huang, Michael Xia, Rajan Anand, Swamy Yeleswaram, Carrie Brodmerkel, Meloni David, Hao Feng, Maryanne Covington, Kris Vaddi, Sharon Diamond, Chu-Biao Xue, Anlai Wang, Ke Zhang, Ganfeng Cao, Brian Metcalf, Robinson Darius J, Lou Storace, Qi Han, Mei Li, Ling Kong, Peggy Scherle, Joseph Glenn, Lixin Shao, Robert C. Newton, Yingxin Zhang, Changsheng Zheng, Steven Friedman, Greg Hollis |
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| Rok vydání: | 2010 |
| Předmět: |
CCR2
Pyrrolidines Receptors CCR2 Clinical Biochemistry Drug Evaluation Preclinical Pharmaceutical Science Administration Oral Pharmacology Biochemistry chemistry.chemical_compound Chemokine receptor Mice Structure-Activity Relationship Drug Discovery Structure–activity relationship Animals Humans Molecular Biology Organic Chemistry Antagonist Chemotaxis Rats chemistry Molecular Medicine Pharmacophore Antagonism Lead compound Protein Binding |
| Zdroj: | Bioorganicmedicinal chemistry letters. 20(24) |
| ISSN: | 1464-3405 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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