1. Design, synthesis and evaluation of MCH receptor 1 antagonists--Part I: Optimization of HTS hits towards an in vivo efficacious tool compound BI 414.
- Author
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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, and Stenkamp D
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Animals, Body Weight drug effects, Cytochrome P-450 CYP2D6 metabolism, Cytochrome P-450 Enzyme Inhibitors chemical synthesis, Cytochrome P-450 Enzyme Inhibitors pharmacology, Drug Design, Eating drug effects, High-Throughput Screening Assays, Obesity drug therapy, Rats, Receptors, G-Protein-Coupled drug effects, Receptors, G-Protein-Coupled metabolism, Structure-Activity Relationship, Alkynes chemical synthesis, Alkynes pharmacology, Anti-Obesity Agents chemical synthesis, Anti-Obesity Agents pharmacology, Pyridines chemical synthesis, Pyridines pharmacology, Receptors, Somatostatin antagonists & inhibitors
- 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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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