Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Xin, Z. et al.

Xin, Serby, Zhao, Kosogof, Szczepankiewicz, Liu, Liu, Hutchins, Sarris, Hoff, Falls, Lin, Ogiela, Collins, Brune, Bush, Droz, Fey, Knourek-Segel, Shapiro, Jacobson, Beno, Turner, Sham, Liu,

Discovery and pharmacological evaluation of growth hormone secretagogue receptor antagonists.

The discovery and pharmacological evaluation of potent, selective, and orally bioavailable growth hormone secretagogue receptor ( GHS-R) antagonists are reported. Previously, 2,4-diaminopyrimidine-based GHS-R antagonists reported from our laboratories have been shown to be dihydrofolate reductase (DHFR) inhibitors. By comparing the X-ray crystal structure of DHFR docked with our GHS-R antagonists and GHS-R modeling, we designed and synthesized a series of potent and DHFR selective GHS-R antagonists with good pharmacokinetic (PK) profiles. An amide derivative 13d (Ca2+ flux IC50 = 188 nM, [brain]/[plasma] = 0.97 @ 8 h in rat) showed a 10% decrease in 24 h food intake in rats, and over 5% body weight reduction after 14-day oral treatment in diet-induced obese (DIO) mice. In comparison, a urea derivative 14c (Ca2+ flux IC50 = 7 nM, [brain]/[plasma] = 0.0 in DIO) failed to show significant effect on food intake in the acute feeding DIO model. These observations demonstrated for the first time that peripheral GHS-R blockage with small molecule GHS-R antagonists might not be sufficient for suppressing appetite and inducing body weight reduction.[1]

References

Discovery and pharmacological evaluation of growth hormone secretagogue receptor antagonists. Xin, Z., Serby, M.D., Zhao, H., Kosogof, C., Szczepankiewicz, B.G., Liu, M., Liu, B., Hutchins, C.W., Sarris, K.A., Hoff, E.D., Falls, H.D., Lin, C.W., Ogiela, C.A., Collins, C.A., Brune, M.E., Bush, E.N., Droz, B.A., Fey, T.A., Knourek-Segel, V.E., Shapiro, R., Jacobson, P.B., Beno, D.W., Turner, T.M., Sham, H.L., Liu, G. J. Med. Chem. (2006) [Pubmed]

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