Identification, Optimization, and Pharmacology of Acylurea GHS-R1a Inverse Agonists

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：July 24, 2014
• 年：2014
• 卷：57
• 期：14
• 页码：6128-6140
• 全文大小：683K
• ISSN：1520-4804

文摘

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鈥揳ctivity 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.