title: Quinazolinone derivatives as orally available ghrelin receptor antagonists for the treatment of diabetes and obesity.
abstract: The peptide hormone ghrelin is the endogenous ligand for the type 1a growth hormone secretagogue receptor (GHS-R1a) and the only currently known circulating appetite stimulant. GHS-R1a antagonism has therefore been proposed as a potential approach for obesity treatment. More recently, ghrelin has been recognized to also play a role in controlling glucose-induced insulin secretion, which suggests another possible benefit for a GHS-R1a antagonist, namely, the role as an insulin secretagogue with potential value for diabetes treatment. In our laboratories, piperidine-substituted quinazolinone derivatives were identified as a new class of small-molecule GHS-R1a antagonists. Starting from an agonist with poor oral bioavailability, optimization led to potent, selective, and orally bioavailable antagonists. In vivo efficacy evaluation of selected compounds revealed suppression of food intake and body weight reduction as well as glucose-lowering effects mediated by glucose-dependent insulin secretion.
authors: Department of Chemistry Research, Bayer Pharmaceuticals Corporation, 400 Morgan Lane, West Haven, Connecticut 06516, USA. rudolph.joachim@gene.com
authors: Joachim
authors: J
authors: Rudolph
authors: William P
authors: WP
authors: Esler
authors: Stephen
authors: S
authors: O'connor
authors: Philip D G
authors: PD
authors: Coish
authors: Philip L
authors: PL
authors: Wickens
authors: Michael
authors: M
authors: Brands
authors: Donald E
authors: DE
authors: Bierer
authors: Brian T
authors: BT
authors: Bloomquist
authors: Georgiy
authors: G
authors: Bondar
authors: Libing
authors: L
authors: Chen
authors: Chih-Yuan
authors: CY
authors: Chuang
authors: Thomas H
authors: TH
authors: Claus
authors: Zahra
authors: Z
authors: Fathi
authors: Wenlang
authors: W
authors: Fu
authors: Uday R
authors: UR
authors: Khire
authors: James A
authors: JA
authors: Kristie
authors: Xiao-Gao
authors: XG
authors: Liu
authors: Derek B
authors: DB
authors: Lowe
authors: Andrea C
authors: AC
authors: McClure
authors: Martin
authors: M
authors: Michels
authors: Astrid A
authors: AA
authors: Ortiz
authors: Philip D
authors: PD
authors: Ramsden
authors: Robert W
authors: RW
authors: Schoenleber
authors: Tatiana E
authors: TE
authors: Shelekhin
authors: Alexandros
authors: A
authors: Vakalopoulos
authors: Weifeng
authors: W
authors: Tang
authors: Lei
authors: L
authors: Wang
authors: Lin
authors: L
authors: Yi
authors: Stephen J
authors: SJ
authors: Gardell
authors: James N
authors: JN
authors: Livingston
authors: Laurel J
authors: LJ
authors: Sweet
authors: William H
authors: WH
authors: Bullock
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001667:Binding, Competitive; D001786:Blood Glucose / Q000032:analysis; D002460:Cell Line; D003920:Diabetes Mellitus / Q000188:drug therapy*; D004435:Eating / Q000187:drug effects; D005951:Glucose Tolerance Test; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy*; D052999:Quinazolinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015431:Weight Loss / Q000187:drug effects
chemical_list: C524277:6-(4-fluorophenoxy)-3-((1-isopropylpiperidin-3-yl)methyl)-2-methylquinazolin-4(3H)-one; C524276:6-(4-fluorophenyl)-2-isopropyl-3-((1-isopropylpiperidin-3-yl)methyl)quinazolin-4(3H)-one; D001786:Blood Glucose; D052999:Quinazolinones; D054440:Receptors, Ghrelin