2,4-Diaminopyrimidine Derivatives as Potent Growth Hormone Secretagogue Receptor Antagonists
Journal of Medicinal Chemistry2006Vol. 49(8), pp. 2568–2578
Citations Over TimeTop 16% of 2006 papers
Michael D. Serby, Hongyu Zhao, Bruce G. Szczepankiewicz, Christi Kosogof, Zhili Xin, Bo Liu, Mei Liu, Lissa T.J. Nelson, Wiweka Kaszubska, Hugh D. Falls, Verlyn G. Schaefer, Eugene N. Bush, Robin Shapiro, Brian A. Droz, Victoria 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
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.
Related Papers
- → Ghrelin, an Endogenous Growth Hormone Secretagogue, Is a Novel Orexigenic Peptide That Antagonizes Leptin Action Through the Activation of Hypothalamic Neuropeptide Y/Y1 Receptor Pathway(2001)856 cited
- → Resistance to the orexigenic effect of ghrelin in dietary-induced obesity in mice: reversal upon weight loss(2004)124 cited
- → Regulation of Growth Hormone Secretagogue Receptor Gene Expression in the Arcuate Nuclei of the Rat by Leptin and Ghrelin(2004)137 cited
- → GSK1614343, a Novel Ghrelin Receptor Antagonist, Produces an Unexpected Increase of Food Intake and Body Weight in Rodents and Dogs(2011)54 cited
- → Effects of ghrelin administration on decreased growth hormone status in obese animals(2007)30 cited