A new class of prolylcarboxypeptidase inhibitors, Part 2: The aminocyclopentanes

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• 作者：Thomas H. Graham^a ; ^{thomas.graham@merck.com} ; Wensheng Liu^a ; Andreas Verras^a ; Mikhail Reibarkh^a ; Kelly Bleasby^b ; Urmi R. Bhatt^c ; Qing Chen^b ; Margarita Garcia-Calvo^c ; Wayne M. Geissler^c ; Judith N. Gorski^d ; Huaibing He^b ; Michael E. Lassman^c ; JeanMarie Lisnock^c ; Xiaohua Li^b ; Zhu Shen^c ; Xinchun Tong^b ; Elaine C. Tung^b ; Judyann Wiltsie^c ; Dan Xie^c ; Suoyu Xu^b ; Jianying Xiao^d ; Jeffrey J. Hale^a ; Shirly Pinto^c ; Dong-Ming Shen^a
• 关键词：Prolylcarboxypeptidase ; PrCP ; Enzyme inhibitor ; Angiotensinase C ; Melanocyte stimulating hormone ; Obesity ; Metabolic syndrome ; Pyrrolidine ; Aminocyclopentane ; High-throughput screening
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 April, 2012
• 卷：22
• 期：8
• 页码：2818-2822
• 文件大小：1867 K

摘要

A series of potent inhibitors of prolylcarboxypeptidase (PrCP) was developed by modifying a lead structure that was discovered by high-throughput screening. The tert-butyl pyrrolidine was replaced by an aminocyclopentane to reduce the metabolic liabilities of the original lead. The compounds demonstrated sub-nanomolar in vitro IC₅₀ values, minimal activity shifts in pure plasma and improved pharmacokinetics. Complete ex vivo plasma target engagement was achieved with low brain exposure at the 20 h time point following p.o. dosing in a mouse. The results indicate that the aminocyclopentanes are useful tools for studying the therapeutic potential of peripheral (non-CNS) PrCP inhibition.