A new class of prolylcarboxypeptidase inhibitors, part 2: the aminocyclopentanes.

Autor: Graham TH; Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065-0900, USA. thomas.graham@merck.com, Liu W, Verras A, Reibarkh M, Bleasby K, Bhatt UR, Chen Q, Garcia-Calvo M, Geissler WM, Gorski JN, He H, Lassman ME, Lisnock J, Li X, Shen Z, Tong X, Tung EC, Wiltsie J, Xie D, Xu S, Xiao J, Hale JJ, Pinto S, Shen DM
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2012 Apr 15; Vol. 22 (8), pp. 2818-22. Date of Electronic Publication: 2012 Mar 01.
DOI: 10.1016/j.bmcl.2012.02.077
Abstrakt: 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 IC(50) 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.
(Copyright © 2012 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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