Identification, optimization, and pharmacology of acylurea GHS-R1a inverse agonists

  • J Med Chem. 2014 Jul 24;57(14):6128-40. doi: 10.1021/jm500610n.
William McCoull  1 ,  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
Affiliations
  • 1. AstraZeneca , Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
PMID: 24967667 DOI: 10.1021/jm500610n
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.

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