Quinazolinone Derivatives as Orally Available Ghrelin Receptor Antagonists for the Treatment of Diabetes and Obesity
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- 作者：Joachim Rudolph ; William P. Esler ; Stephen O'Connor ; Philip D. G. Coish ; Philip L. Wickens ; Michael Brands ; Donald E. Bierer ; Brian T. Bloomquist ; Georgiy Bondar ; Libing Chen ; Chih-Yuan Chuang ; Thomas
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：October 18, 2007
- 年：2007
- 卷：50
- 期：21
- 页码：5202 - 5216
- 全文大小：465K
- 年卷期：v.50,no.21(October 18, 2007)
- ISSN：1520-4804
文摘
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 thereforebeen proposed as a potential approach for obesity treatment. More recently, ghrelin has been recognized toalso play a role in controlling glucose-induced insulin secretion, which suggests another possible benefit fora 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 topotent, selective, and orally bioavailable antagonists. In vivo efficacy evaluation of selected compoundsrevealed suppression of food intake and body weight reduction as well as glucose-lowering effects mediatedby glucose-dependent insulin secretion.