Design, synthesis and evaluation of MCH receptor 1 antagonists--Part I: Optimization of HTS hits towards an in vivo efficacious tool compound BI 414.
Basic Information
ID: ALA3600293
Journal: Bioorg Med Chem Lett
Title: Design, synthesis and evaluation of MCH receptor 1 antagonists--Part I: Optimization of HTS hits towards an in vivo efficacious tool compound BI 414.
Authors: Müller SG, Heckel A, Kley JT, Lehmann T, Lustenberger P, Oost T, Roth GJ, Rudolf K, Arndt K, Lenter M, Lotz RR, Maier GM, Markert M, Schindler M, Stenkamp D.
Abstract: Despite recent approvals of anti-obesity drugs there is still a high therapeutic need for alternative options with higher efficacy in humans. As part of our MCH-R1 antagonist program for the treatment of obesity, a series of biphenylacetamide HTS hits was evaluated. Several issues of the initial lead structures had to be resolved, such as potency, selectivity over related GPCRs and P-gp efflux limiting brain exposure in this series. We could demonstrate that all parameters can be significantly improved by structural modifications resulting in BI 414 as a potent and orally available MCH-R1 antagonist tool compound with acceptable in vivo efficacy in an animal model of obesity.
CiteXplore: 26112443
DOI: 10.1016/j.bmcl.2015.05.077
Patent ID: ┄