McCoull, W, Barton, P, Brown, AJ, Bowker, SS, Cameron, J, Clarke, DS, Davies, RD, Dossetter, AG, Ertan, A, Fenwick, M, Green, C, Holmes, JL, Martin, N, Masters, D, Moore, JE, Newcombe, NJ, Newton, C, Pointon, H, Robb, GR, Sheldon, C, Stokes, S and Morgan, D (2014) Identification, optimization, and pharmacology of acylurea GHS-R1a inverse agonists. Journal of Medicinal Chemistry, 57 (14). 6128 - 6140. ISSN 1520-4804

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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.

Item Type: Article
Uncontrolled Keywords: dose-response relationship, drug, drug inverse agonism, humans, models, molecular, molecular structure, receptors, Ghrelin, Structure-Activity Relationship, urea
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculty of Medicine and Health Sciences > Institute for Science and Technology in Medicine
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Depositing User: Symplectic
Date Deposited: 09 Jun 2016 08:25
Last Modified: 09 Jun 2016 08:25

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