Journal of Medicinal Chemistry 2006-04-20

2,4-diaminopyrimidine derivatives as potent growth hormone secretagogue receptor antagonists.

Michael D Serby, Hongyu Zhao, Bruce G Szczepankiewicz, Christi Kosogof, Zhili Xin, Bo Liu, Mei Liu, Lissa T J Nelson, Wiweka Kaszubska, H Douglas Falls, Verlyn Schaefer, Eugene N Bush, Robin Shapiro, Brian A Droz, Victoria E Knourek-Segel, Thomas A Fey, Michael E Brune, David W A Beno, Theresa M Turner, Christine A Collins, Peer B Jacobson, Hing L Sham, Gang Liu

Index: J. Med. Chem. 49(8) , 2568-78, (2006)

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Abstract

Ghrelin, a gut-derived orexigenic hormone, is an endogenous ligand of the growth hormone secretagogue receptor (GHS-R). Centrally administered ghrelin has been shown to cause hunger and increase food intake in rodents. Inhibition of ghrelin actions with ghrelin antibody, peptidyl GHS-R antagonists, and antisense oligonucleosides resulted in weight loss and food intake decrease in rodents. Here we report the effects of GHS-R antagonists, some of which were potent, selective, and orally bioavailable. A structure-activity relationship study led to the discovery of 8a, which was effective in decreasing food intake and body weight in several acute rat studies.