Non-basic azolotriazinone MCHR1 antagonists for the treatment of obesity: An empirical brain-exposures-driven candidate selection for in vivo efficacy studies.

Abstract

Non-basic azolotriazinones were explored using an empirical free brain exposures-driven approach to identify potent MCHR1 antagonists for evaluation in in vivo efficacy studies. An optimized lead from this series, 1j (rMCHR1 Ki=1.8 nM), demonstrated a 6.9% reduction in weight gain relative to vehicle in a rat model at 30 mg/kg after 4 days of once-daily oral treatment as a glycine prodrug. Despite a promising efficacy profile, an assessment of the biliary toxicity risk of this compound rendered this compound non-progressible.

• Authors: Pratik Devasthale, Wei Wang, James Mignone, Kishore Renduchintala, Sridhar Radhakrishnan, Jayanthi Dhanapal, Jagannath Selvaraj, Rajesh Kuppusamy, Mary Ann Pelleymounter, Daniel Longhi, Ning Huang, Neil Flynn, Anthony V Azzara, Kenneth Rohrbach, James Devenny, Suzanne Rooney, Michael Thomas, Susan Glick, Helen Godonis, Susan Harvey, Mary Jane Cullen, Hongwei Zhang, Christian Caporuscio, Paul Stetsko, Mary Grubb, Christine Huang, Lisa Zhang, Chris Freeden, Brian J Murphy, Jeffrey A Robl, William N Washburn
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 25 Issue 20 Pg. 4412-8 (Oct 15 2015) ISSN: 1464-3405 [Electronic] England
• PMID: 26386604 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• MCHR1 protein, human
• Receptors, Somatostatin
• Triazines
• azolotriazinone

Topics

• Animals
• Brain (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Humans
• Molecular Structure
• Obesity (drug therapy, metabolism)
• Rats
• Receptors, Somatostatin (antagonists & inhibitors)
• Structure-Activity Relationship
• Triazines (administration & dosage, chemistry, pharmacology)