A new class of prolylcarboxypeptidase inhibitors, Part 1: Discovery and evaluation

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• 作者：Thomas H. Graham^a ; ^{thomas.graham@merck.com} ; Wensheng Liu^a ; Andreas Verras^a ; Iyassu K. Sebhat^a ; Yusheng Xiong^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 ; Jianying Xiao^d ; Dan Xie^c ; Suoyu Xu^b ; 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：2811-2817
• 文件大小：3190 K

摘要

A new structural class of potent prolylcarboxypeptidase (PrCP) inhibitors was discovered by high-throughput screening. The series possesses a tractable SAR profile with sub-nanomolar in vitro IC₅₀ values. Compared to prior inhibitors, the new series demonstrated minimal activity shifts in pure plasma and complete ex vivo plasma target engagement in mouse plasma at the 20 h post-dose time point (po). In addition, the in vivo level of CNS and non-CNS drug exposure was measured.