Design, synthesis and evaluation of MCH receptor 1 antagonists--Part III: Discovery of pre-clinical development candidate BI 186908.

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.

• Authors: Thorsten Oost, Armin Heckel, Jörg T Kley, Thorsten Lehmann, Stephan Müller, Gerald J Roth, Klaus Rudolf, Kirsten Arndt, Ralph Budzinski, Martin Lenter, Ralf R H Lotz, Gerd-Michael Maier, Michael Markert, Leo Thomas, Dirk Stenkamp
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 25 Issue 16 Pg. 3275-80 (Aug 15 2015) ISSN: 1464-3405 [Electronic] England
• PMID: 26105194 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Anti-Obesity Agents
• Appetite Depressants
• BI 186908
• Cyclobutanes
• Ether-A-Go-Go Potassium Channels
• MCHR1 protein, rat
• Phospholipids
• Potassium Channel Blockers
• Pyrazines
• Pyridazines
• Pyridines
• Receptors, Somatostatin
• sibutramine

Topics

• Animals
• Anti-Obesity Agents (chemical synthesis, pharmacology)
• 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, pharmacology)
• Pyrazines (chemical synthesis, pharmacology)
• Pyridazines (chemical synthesis, pharmacology)
• Pyridines (chemical synthesis, pharmacology)
• Rats
• Receptors, Somatostatin (antagonists & inhibitors)
• Structure-Activity Relationship