2. Academic Validation
  3. Identification, optimization, and pharmacology of acylurea GHS-R1a inverse agonists

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

Affiliation

  • 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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