Discovery of a novel series of melanin-concentrating hormone receptor 1 antagonists for the treatment of obesity

Jeffrey T Mihalic; Xiaoqi Chen; Pingchen Fan; Xi Chen; Ying Fu; Lingming Liang; Michael Reed; Liang Tang; Jin-Long Chen; Juan Jaen; Leping Li; Kang Dai

doi:10.1016/j.bmcl.2011.09.110

Discovery of a novel series of melanin-concentrating hormone receptor 1 antagonists for the treatment of obesity

Bioorg Med Chem Lett. 2011 Dec 1;21(23):7001-5. doi: 10.1016/j.bmcl.2011.09.110. Epub 2011 Oct 5.

Authors

Jeffrey T Mihalic¹, Xiaoqi Chen, Pingchen Fan, Xi Chen, Ying Fu, Lingming Liang, Michael Reed, Liang Tang, Jin-Long Chen, Juan Jaen, Leping Li, Kang Dai

Affiliation

¹ Department of Medicinal Chemistry, Amgen, South San Francisco, CA 94080, USA. jmihalic@amgen.com

PMID: 22019296
DOI: 10.1016/j.bmcl.2011.09.110

Abstract

A new class of MCHR1 antagonists was discovered via a high-throughput screen. Optimization of the lead structure resulted in the identification of indole 10e. This compound possesses good pharmacokinetic properties across preclinical species and is efficacious in reducing food consumption in an MCH cannulated rat model and a cynomolgus monkey food consumption model.

MeSH terms

Animals
Anti-Obesity Agents / chemical synthesis
Anti-Obesity Agents / chemistry*
Anti-Obesity Agents / pharmacokinetics
Anti-Obesity Agents / pharmacology
Dogs
Drug Discovery*
Eating / drug effects
HEK293 Cells
Humans
Indoles / chemical synthesis
Indoles / chemistry*
Indoles / pharmacology
Inhibitory Concentration 50
Macaca mulatta
Molecular Structure
Rats
Receptors, Pituitary Hormone / antagonists & inhibitors*
Structure-Activity Relationship

Substances

Anti-Obesity Agents
Indoles
Receptors, Pituitary Hormone
melanin-concentrating hormone receptor
indole