Design, synthesis and evaluation of MCH receptor 1 antagonists--Part I: Optimization of HTS hits towards an in vivo efficacious tool compound BI 414

Stephan G Müller; Armin Heckel; Jörg T Kley; Thorsten Lehmann; Philipp Lustenberger; Thorsten Oost; Gerald J Roth; Klaus Rudolf; Kirsten Arndt; Martin Lenter; Ralf R H Lotz; Gerd-Michael Maier; Michael Markert; Marcus Schindler; Dirk Stenkamp

doi:10.1016/j.bmcl.2015.05.077

Design, synthesis and evaluation of MCH receptor 1 antagonists--Part I: Optimization of HTS hits towards an in vivo efficacious tool compound BI 414

Bioorg Med Chem Lett. 2015 Aug 15;25(16):3264-9. doi: 10.1016/j.bmcl.2015.05.077. Epub 2015 Jun 6.

Authors

Affiliations

¹ Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Medicinal Chemistry, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany. Electronic address: stephan_georg.mueller@boehringer-ingelheim.com.
² Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Medicinal Chemistry, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany.
³ Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Cardiometabolic Research, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany.
⁴ Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Drug Discovery Support Research Germany, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany.

PMID: 26112443
DOI: 10.1016/j.bmcl.2015.05.077

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.

Keywords: Alkynes; MCH-R1 antagonists; Melanin-concentrating hormone (MCH).

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
Alkynes / chemical synthesis*
Alkynes / pharmacology*
Animals
Anti-Obesity Agents / chemical synthesis*
Anti-Obesity Agents / pharmacology*
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
Pyridines / chemical synthesis*
Pyridines / pharmacology*
Rats
Receptors, G-Protein-Coupled / drug effects
Receptors, G-Protein-Coupled / metabolism
Receptors, Somatostatin / antagonists & inhibitors*
Structure-Activity Relationship

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Alkynes
Anti-Obesity Agents
BI 414
Cytochrome P-450 Enzyme Inhibitors
MCHR1 protein, rat
Pyridines
Receptors, G-Protein-Coupled
Receptors, Somatostatin
Cytochrome P-450 CYP2D6