Identification, optimization, and pharmacology of acylurea GHS-R1a inverse agonists

McCoull, William; Barton, Peter; Brown, Alastair J.H.; Bowker, Suzanne S.; Cameron, Jennifer; Clarke, David S.; Davies, Robert D.M.; Dossetter, Alexander G.; Ertan, Anne; Fenwick, Mark; Green, Clive; Holmes, Jane L.; Martin, Nathaniel; Masters, David; Moore, Jane E.; Newcombe, Nicholas J.; Newton, Claire; Pointon, Helen; Robb, Graeme R.; Sheldon, Christopher; Stokes, Stephen; Morgan, David

Abstract

Ghrelin plays a major physiological role in the control of food intake, and inverse agonists of the ghrelin receptor (GHS-R1a) are widely considered to offer utility as antiobesity agents by lowering the set-point for hunger between meals. We identified an acylurea series of ghrelin modulators from high throughput screening and optimized binding affinity through structure-activity relationship studies. Furthermore, we identified specific substructural changes, which switched partial agonist activity to inverse agonist activity, and optimized physicochemical and DMPK properties to afford the non-CNS penetrant inverse agonist 22 (AZ-GHS-22) and the CNS penetrant inverse agonist 38 (AZ-GHS-38). Free feeding efficacy experiments showed that CNS exposure was necessary to obtain reduced food intake in mice, and it was demonstrated using GHS-R1a null and wild-type mice that this effect operates through a mechanism involving GHS-R1a.

• Journal Article Type: Article
• Acceptance Date: Apr 18, 2014
• Online Publication Date: Jul 24, 2014
• Publication Date: Jul 24, 2014
• Journal: Journal of Medicinal Chemistry
• Print ISSN: 0022-2623
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 57
• Issue: 14
• Pages: 6128 - 6140
• Keywords: dose-response relationship, drug, drug inverse agonism, humans, models, molecular, molecular structure, receptors, Ghrelin, Structure-Activity Relationship, urea
• Publisher URL: http://dx.doi.org/10.1021/jm500610n