Discovery of a new class of ghrelin receptor antagonists

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• 作者：Jeffrey T. Mihalic ; ^{jmihalic@amgen.com} ; Yong-Jae Kim ; Mike Lizarzaburu ; Xiaoqi Chen ; Jeff Deignan ; Malgorzata Wanska ; Ming Yu ; Jiasheng Fu ; Xi Chen ; Alex Zhang ; Richard Connors ; Lingming Liang ; Michelle Lindstrom ; Ji Ma ; Liang Tang ; Kang Dai ; Leping Li
• 关键词：Ghrelin ; GHSR1a ; Obesity
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：1 March, 2012
• 年：2012
• 卷：22
• 期：5
• 页码：2046-2051
• 全文大小：1483 K

文摘

A series of benzodiazepine antagonists of the human ghrelin receptor GHSR1a were synthesized and their antagonism and metabolic stability were evaluated. The potency of these analogs was determined using a functional aequorin (Euroscreen) luminescent assay measuring the intracellular Ca²⁺ concentration, and their metabolic stability was measured using an in vitro rat and human S9 hepatocyte assay. These efforts led to the discovery of a potent ghrelin antagonist with good rat pharmacokinetic properties.