ABSTRACT
Although overweight and obesity are highly prevalent conditions, options to treat them are still very limited. As part of our search for safe and effective MCH-R1 antagonists for the treatment of obesity, two series of pyridones and pyridazinones were evaluated. Optimization was aimed at improving DMPK properties by increasing metabolic stability and improving the safety profile by reducing inhibition of the hERG channel and reducing the potential to induce phospholipidosis. Steric shielding of a labile keto moiety with an ortho-methyl group and fine-tuning of the polarity in several parts of the molecule resulted in BI 186908 (11 g), a potent and selective MCH-R1 antagonist with favorable DMPK and CMC properties. Chronic administration of BI 186908 resulted in significant body weight reduction comparable to sibutramine in a 4 week diet-induced obesity model in rats. Based on its favorable safety profile, BI 186908 was advanced to pre-clinical development.
Subject(s)
Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacology , Pyridazines/chemical synthesis , Pyridazines/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Animals , Appetite Depressants/pharmacology , Body Weight/drug effects , Cyclobutanes/pharmacology , Drug Discovery , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Hepatocytes/metabolism , High-Throughput Screening Assays , Humans , In Vitro Techniques , Lipidoses/drug therapy , Microsomes, Liver/metabolism , Phospholipids/metabolism , Potassium Channel Blockers/chemical synthesis , Potassium Channel Blockers/pharmacology , Pyrazines/chemical synthesis , Pyrazines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Alkynes/chemical synthesis , Alkynes/pharmacology , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , 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 RelationshipABSTRACT
Despite recent success there remains a high therapeutic need for the development of drugs targeting diseases associated with the metabolic syndrome. As part of our search for safe and effective MCH-R1 antagonists for the treatment of obesity, a series of 3,6-disubstituted pyridazines was evaluated. During optimization several issues of the initial lead structures had to be resolved, such as selectivity over related GPCRs, inhibition of the hERG channel as well as the potential to induce phospholipidosis. Utilizing property-based design, we could demonstrate that all parameters can significantly be improved by consequently increasing the polarity of the compounds. By this strategy, we succeeded in identifying potent and orally available MCH-R1 antagonists with good selectivity over M1 and 5-HT2A and an improved safety profile with respect to hERG inhibition and phospholipidosis.
