McCoull, W and Barton, P and Brown, AJ and Bowker, SS and Cameron, J and Clarke, DS and Davies, RD and Dossetter, AG and Ertan, A and Fenwick, M and Green, C and Holmes, JL and Martin, N and Masters, D and Moore, JE and Newcombe, NJ and Newton, C and Pointon, H and Robb, GR and Sheldon, C and 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

[img] Text
ghrelin_AU_sulfones_JMC_WM10Mar14_formatted.docx - Accepted Version
Restricted to Repository staff only
Available under License Creative Commons Attribution.

Download (1MB)

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.

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
Related URLs:
Depositing User: Symplectic
Date Deposited: 09 Jun 2016 08:25
Last Modified: 09 Jun 2016 08:25
URI: http://eprints.keele.ac.uk/id/eprint/1716

Actions (login required)

View Item View Item