Discovery, Optimization, and Pharmacological Characterization of Novel Heteroaroylphenylureas Antagonists of C-C Chemokine Ligand 2 Function

作者：Laborde Edgardo^*; Macsata Robert W; Meng Fanying; Peterson Brian T; Robinson Louise; Schow Steve R; Simon Reyna J; Xu Hua; Baba Kunihisa; Inagaki Hideaki; Ishiwata Yoshiro; Jomori Takahito; Matsumoto Yukiharu; Miyachi Atsushi; Nakamura Takashi; Okamoto Masayuki; Handel Tracy M; Bernard Claude C A

来源：Journal of Medicinal Chemistry, 2011, 54(6): 1667-1681.

DOI：10.1021/jm1012903

Through the application of TRAP (target-related affinity profiling), we identified a novel class of heteroaroylphenylureas that inhibit human CCL2-induced chemotaxis of monocytes/macrophages both in vitro and in vivo. This inhibition was concentration-dependent and selective with regard to other chemokines. The compounds, however, did not antagonize the binding of (125)I-labeled CCL2 to the CCR2 receptor nor did they block CCR2-mediated signal transduction responses such as calcium mobilization. Optimization of early leads for potency and pharmacokinetic parameters resulted in the identification of 17, a potent inhibitor of chemotaxis (IC(50) = 80 nM) with excellent oral bioavailability in rats (F = 60%). Compound 17 reduced swelling and joint destruction in two rat models of rheumatoid arthritis and delayed disease onset and produced near complete resolution of symptoms in a mouse model of multiple sclerosis.

• 出版日期2011-3-24