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

Andrew J. Souers,* Ju Gao, Michael Brune, Eugene Bush, Dariusz Wodka, Anil Vasudevan, Andrew S. Judd, Mathew Mulhern, Sevan Brodjian, Brian Dayton, Robin Shapiro, Lisa E. Hernandez, Kennan C. Marsh, Hing L. Sham, Christine A. Collins, and Philip R. Kym
Metabolic Disease Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064
J. Med. Chem., 2005, 48 (5), pp 1318–1321
DOI: 10.1021/jm0490890
Publication Date (Web): February 15, 2005
Copyright © 2005 American Chemical Society
*

 To whom correspondence should be addressed. Phone:  847-937-5312. Fax:  847-938-1674. E-mail:  andrew.souers@abbott.com.

Abstract

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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

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  • Published In Issue March 10, 2005
  • Received November 11, 2004

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