Non-basic azolotriazinone MCHR1 antagonists for the treatment of obesity: An empirical brain-exposures-driven candidate selection for in vivo efficacy studies. Issue 20 (15th October 2015)

• Record Type: Journal Article
• Authors: Devasthale, Pratik; Wang, Wei; Mignone, James; Renduchintala, Kishore; Radhakrishnan, Sridhar; Dhanapal, Jayanthi; Selvaraj, Jagannath; Kuppusamy, Rajesh; Pelleymounter, Mary Ann; Longhi, Daniel; Huang, Ning; Flynn, Neil; Azzara, Anthony V.; Rohrbach, Kenneth; Devenny, James; Rooney, Suzanne; Thomas, Michael; Glick, Susan; Godonis, Helen; Harvey, Susan; Cullen, Mary Jane; Zhang, Hongwei; Caporuscio, Christian; Stetsko, Paul; Grubb, Mary; Huang, Christine; Zhang, Lisa; Freeden, Chris; Murphy, Brian J.; Robl, Jeffrey A.; Washburn, William N.;
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 20(2015)
• Page Start: 4412
• Page End: 4418
• Publication Date: 2015-10-15
• Subjects: Non-basic MCHR1 antagonists -- Anti-obesity -- Off-rates -- Biliary toxicity -- Metabolite toxicity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.09.018
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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 K i = 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.