Discovery and Pharmacological Evaluation of Growth Hormone Secretagogue Receptor Antagonists

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• 作者：Zhili Xin ; Michael D. Serby ; Hongyu Zhao ; Christi Kosogof ; Bruce G. Szczepankiewicz ; Mei Liu ; BoLiu ; Charles W. Hutchins ; Kathy A. Sarris ; Ethan D. Hoff ; H. Douglas Falls ; Chun W. Lin ; Christopher A.
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：July 27, 2006
• 年：2006
• 卷：49
• 期：15
• 页码：4459 - 4469
• 全文大小：335K
• 年卷期：v.49,no.15(July 27, 2006)
• ISSN：1520-4804

文摘

The discovery and pharmacological evaluation of potent, selective, and orally bioavailable growth hormonesecretagogue receptor (GHS-R) antagonists are reported. Previously, 2,4-diaminopyrimidine-based GHS-Rantagonists 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 goodpharmacokinetic (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 reductionafter 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 theacute feeding DIO model. These observations demonstrated for the first time that peripheral GHS-R blockagewith small molecule GHS-R antagonists might not be sufficient for suppressing appetite and inducing bodyweight reduction.