1. Identification, Optimization, and Pharmacology of Acylurea GHS-R1a Inverse Agonists
- Author
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Suzanne S. Bowker, Clive Green, Graeme R. Robb, Stephen Stokes, Nathaniel G. Martin, Anne Ertan, David G.A. Morgan, Christopher Sheldon, Alexander G. Dossetter, Robert D. M. Davies, David S. Clarke, Alastair J. H. Brown, William McCoull, Helen Pointon, Jane E. Moore, Mark L. Fenwick, Nicholas John Newcombe, Claire Newton, Jane L. Holmes, David J. Masters, Peter Barton, and Jennifer Cameron
- Subjects
Models, Molecular ,medicine.medical_specialty ,Drug Inverse Agonism ,High-throughput screening ,Pharmacology ,Partial agonist ,Structure-Activity Relationship ,chemistry.chemical_compound ,Internal medicine ,Drug Discovery ,medicine ,Humans ,Urea ,Inverse agonist ,Structure–activity relationship ,Receptors, Ghrelin ,Receptor ,Dose-Response Relationship, Drug ,Molecular Structure ,digestive, oral, and skin physiology ,Endocrinology ,chemistry ,Molecular Medicine ,Ghrelin ,Penetrant (biochemical) ,hormones, hormone substitutes, and hormone antagonists - 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.
- Published
- 2014