Design, synthesis and evaluation of MCH receptor 1 antagonists—Part I: Optimization of HTS hits towards an in vivo efficacious tool compound BI 414. Issue 16 (15th August 2015)

• Record Type: Journal Article
• Authors: Müller, Stephan G.; Heckel, Armin; Kley, Jörg T.; Lehmann, Thorsten; Lustenberger, Philipp; Oost, Thorsten; Roth, Gerald J.; Rudolf, Klaus; Arndt, Kirsten; Lenter, Martin; Lotz, Ralf R.H.; Maier, Gerd-Michael; Markert, Michael; Schindler, Marcus; Stenkamp, Dirk
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 16(2015)
• Page Start: 3264
• Page End: 3269
• Publication Date: 2015-08-15
• Subjects: Melanin-concentrating hormone (MCH) -- MCH-R1 antagonists -- Alkynes; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.05.077
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.