Document Report Card

ID: ALA1949557

Journal: ACS Med Chem Lett

Title: Discovery of INCB3284, a Potent, Selective, and Orally Bioavailable hCCR2 Antagonist.

Authors: Xue CB, Feng H, Cao G, Huang T, Glenn J, Anand R, Meloni D, Zhang K, Kong L, Wang A, Zhang Y, Zheng C, Xia M, Chen L, Tanaka H, Han Q, Robinson DJ, Modi D, Storace L, Shao L, Sharief V, Li M, Galya LG, Covington M, Scherle P, Diamond S, Emm T, Yeleswaram S, Contel N, Vaddi K, Newton R, Hollis G, Friedman S, Metcalf B.

Abstract: We report the identification of 13 (INCB3284) as a potent human CCR2 (hCCR2) antagonist. INCB3284 exhibited an IC50 of 3.7 nM in antagonism of monocyte chemoattractant protein-1 binding to hCCR2, an IC50 of 4.7 nM in antagonism of chemotaxis activity, an IC50 of 84 μM in inhibition of the hERG potassium current, a free fraction of 58% in protein binding, high selectivity over other chemokine receptors and G-protein-coupled receptors, and acceptable oral bioavailability in rodents and primates. In human clinical trials, INCB3284 exhibited a pharmacokinetic profile suitable for once-a-day dosing (T 1/2 = 15 h).

CiteXplore: 24900329

DOI: 10.1021/ml200030q