Design and Synthesis of Prolylcarboxypeptidase (PrCP) Inhibitors To Validate PrCP As A Potential Target for Obesity

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• 作者：Changyou Zhou ; Margareta Garcia-Calvo ; Shirly Pinto ; Matthew Lombardo ; Zhe Feng ; Kate Bender ; KellyAnn D. Pryor ; Urmi R. Bhatt ; Renee M. Chabin ; Wayne M. Geissler ; Zhu Shen ; Xinchun Tong ; Zhoupeng Zha
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：October 14, 2010
• 年：2010
• 卷：53
• 期：19
• 页码：7251-7263
• 全文大小：1105K
• 年卷期：v.53,no.19(October 14, 2010)
• ISSN：1520-4804

文摘

Prolylcarboxypeptidase (PrCP) is a serine protease that may have a role in metabolism regulation. A class of reversible, potent, and selective PrCP inhibitors was developed starting from a mechanism based design for inhibiting this serine protease. Compound 8o inhibits human and mouse PrCP at IC₅₀ values of 1 and 2 nM and is not active (IC₅₀ > 25 μM) against a panel of closely related proteases. It has lower serum binding than its close analogues and is bioavailable in mouse. Subchronic dosing of 8o in PrCP^−/− and WT mice at 100 mg/kg for 5 days resulted in a 5% reduction in body weight in WT mice and a 1% reduction in PrCP KO mice.