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Identification of 2-(4-Benzyloxyphenyl)- N - [1-(2-pyrrolidin-1-yl-ethyl)-1 H -indazol-6-yl]acetamide, an Orally Efficacious Melanin-Concentrating Hormone Receptor 1 Antagonist for the Treatment of Obesity

2005; American Chemical Society; Volume: 48; Issue: 5 Linguagem: Inglês

10.1021/jm0490890

1520-4804

Andrew J. Souers, Ju Gao, Michael E. Brune, Eugene N. Bush, Dariusz Wódka, Anil Vasudevan, Andrew S. Judd, Mathew M. Mulhern, Sevan Brodjian, Brian D. Dayton, Robin Shapiro, Lisa E. Hernandez, Kennan C. Marsh, Hing L. Sham, Christine A. Collins, Philip R. Kym,

Adipose Tissue and Metabolism

Optimization of a high-throughput screening hit against melanin-concentrating hormone receptor 1 (MCHr1) led to the discovery of 2-(4-benzyloxy-phenyl)-N-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-yl]acetamide (7a). This compound was found to be a high-affinity ligand for MCHr1 and a potent inhibitor of MCH-mediated Ca2+ release, showed good plasma and CNS exposure upon oral dosing in diet-induced obese mice, and is the first reported MCHr1 antagonist that is efficacious upon oral dosing in a chronic model of weight loss.1