title: Identification, optimization, and pharmacology of acylurea GHS-R1a inverse agonists.
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.
authors: AstraZeneca , Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors: William
authors: W
authors: McCoull
authors: Peter
authors: P
authors: Barton
authors: Alastair J H
authors: AJ
authors: Brown
authors: Suzanne S
authors: SS
authors: Bowker
authors: Jennifer
authors: J
authors: Cameron
authors: David S
authors: DS
authors: Clarke
authors: Robert D M
authors: RD
authors: Davies
authors: Alexander G
authors: AG
authors: Dossetter
authors: Anne
authors: A
authors: Ertan
authors: Mark
authors: M
authors: Fenwick
authors: Clive
authors: C
authors: Green
authors: Jane L
authors: JL
authors: Holmes
authors: Nathaniel
authors: N
authors: Martin
authors: David
authors: D
authors: Masters
authors: Jane E
authors: JE
authors: Moore
authors: Nicholas J
authors: NJ
authors: Newcombe
authors: Claire
authors: C
authors: Newton
authors: Helen
authors: H
authors: Pointon
authors: Graeme R
authors: GR
authors: Robb
authors: Christopher
authors: C
authors: Sheldon
authors: Stephen
authors: S
authors: Stokes
authors: David
authors: D
authors: Morgan
mesh_terms: D004305:Dose-Response Relationship, Drug; D054314:Drug Inverse Agonism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D054440:Receptors, Ghrelin / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D054440:Receptors, Ghrelin; D014508:Urea