Synthesis and Pharmacological in Vitro and in Vivo Evaluations of Novel Triazole Derivatives as Ligands of the Ghrelin Receptor. 1

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• 作者：Luc Demange ; Damien Boeglin ; Aline Moulin ; Delphine Mousseaux ; Joanne Ryan ; Gilbert Berg&eacute ; Didier Gagne ; Annie Heitz ; Daniel Perrissoud ; Vittorio Locatelli ; Antonio Torsello ; Jean-Claude Galley
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：April 19, 2007
• 年：2007
• 卷：50
• 期：8
• 页码：1939 - 1957
• 全文大小：285K
• 年卷期：v.50,no.8(April 19, 2007)
• ISSN：1520-4804

文摘

A new series of growth hormone secretagogue (GHS) analogues based on the 1,2,4-triazole structure weresynthesized and evaluated for their in vitro binding and their ability to stimulate intracellular calcium releaseto the cloned hGHS-1a ghrelin receptor expressed in LLC PK-1 cells. We have synthesized potent ligandsof this receptor, some of them behaving as agonists, partial agonists, or antagonists. Some compounds amongthe most potent, i.e., agonist 29c (JMV2873), partial agonists including 21b (JMV2810), antagonists 19b(JMV2866) and 19c (JMV2844), were evaluated for their in vivo activity on food intake, after sc injectionin rodents. Some compounds were found to stimulate food intake like hexarelin; some others were identifiedas potent hexarelin antagonists in this assay. Among the tested compounds, 21b was identified as an invitro ghrelin receptor partial agonist, as well as a potent in vivo antagonist of hexarelin-stimulated foodintake in rodents. Compound 21b was without effect on GH release from rat. However, in this series ofcompounds, it was not possible to find a clear correlation between in vitro and in vivo results.