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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


William McCoull

Peter Barton

Alastair J.H. Brown

Suzanne S. Bowker

Jennifer Cameron

David S. Clarke

Robert D.M. Davies

Alexander G. Dossetter

Anne Ertan

Mark Fenwick

Clive Green

Jane L. Holmes

Nathaniel Martin

David Masters

Jane E. Moore

Nicholas J. Newcombe

Claire Newton

Helen Pointon

Graeme R. Robb

Christopher Sheldon

Stephen Stokes

David Morgan


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
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