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Design, synthesis and evaluation of MCH receptor 1 antagonists--Part I: Optimization of HTS hits towards an in vivo efficacious tool compound BI 414.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2015 Aug 15; Vol. 25 (16), pp. 3264-9. Date of Electronic Publication: 2015 Jun 06. - Publication Year :
- 2015
-
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.<br /> (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 25
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 26112443
- Full Text :
- https://doi.org/10.1016/j.bmcl.2015.05.077