Document Report Card

ID: ALA1148824

Journal: J Med Chem

Title: Quinazolinone derivatives as orally available ghrelin receptor antagonists for the treatment of diabetes and obesity.

Authors: Rudolph J, Esler WP, O'connor S, Coish PD, Wickens PL, Brands M, Bierer DE, Bloomquist BT, Bondar G, Chen L, Chuang CY, Claus TH, Fathi Z, Fu W, Khire UR, Kristie JA, Liu XG, Lowe DB, McClure AC, Michels M, Ortiz AA, Ramsden PD, Schoenleber RW, Shelekhin TE, Vakalopoulos A, Tang W, Wang L, Yi L, Gardell SJ, Livingston JN, Sweet LJ, Bullock WH.

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.

CiteXplore: 17887659

DOI: 10.1021/jm070071+