Discovery and pharmacological evaluation of growth hormone secretagogue receptor antagonists

被引：41

作者：

Xin, Zhili ^{[1
]}

Serby, Michael D. ^{[1
]}

Zhao, Hongyu ^{[1
]}

Kosogof, Christi ^{[1
]}

Szczepankiewicz, Bruce G. ^{[1
]}

Liu, Mei ^{[1
]}

Liu, Bo ^{[1
]}

Hutchins, Charles W. ^{[1
]}

Sarris, Kathy A. ^{[1
]}

Hoff, Ethan D. ^{[1
]}

Falls, H. Douglas ^{[1
]}

Lin, Chun W. ^{[1
]}

Ogiela, Christopher A. ^{[1
]}

Collins, Christine A. ^{[1
]}

Brune, Michael E. ^{[1
]}

Bush, Eugene N. ^{[1
]}

Droz, Brian A. ^{[1
]}

Fey, Thomas A. ^{[1
]}

Knourek-Segel, Victoria E. ^{[1
]}

Shapiro, Robin ^{[1
]}

Jacobson, Peer B. ^{[1
]}

Beno, David W. A. ^{[1
]}

Turner, Teresa M. ^{[1
]}

Sham, Hing L. ^{[1
]}

Liu, Gang ^{[1
]}

机构：

[1] Abbott Labs, Metab Dis Res, Global Pharmaceut Res & Dev, Abbott Pk, IL 60064 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 15期

关键词：

D O I：

10.1021/jm060461g

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：4459 / 4469

页数：11

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