title: A new class of prolylcarboxypeptidase inhibitors, part 2: the aminocyclopentanes.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065-0900, USA. thomas.graham@merck.com
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Graham
authors.forename: Wensheng
authors.initials: W
authors.lastname: Liu
authors.forename: Andreas
authors.initials: A
authors.lastname: Verras
authors.forename: Mikhail
authors.initials: M
authors.lastname: Reibarkh
authors.forename: Kelly
authors.initials: K
authors.lastname: Bleasby
authors.forename: Urmi R
authors.initials: UR
authors.lastname: Bhatt
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.forename: Margarita
authors.initials: M
authors.lastname: Garcia-Calvo
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Geissler
authors.forename: Judith N
authors.initials: JN
authors.lastname: Gorski
authors.forename: Huaibing
authors.initials: H
authors.lastname: He
authors.forename: Michael E
authors.initials: ME
authors.lastname: Lassman
authors.forename: JeanMarie
authors.initials: J
authors.lastname: Lisnock
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Li
authors.forename: Zhu
authors.initials: Z
authors.lastname: Shen
authors.forename: Xinchun
authors.initials: X
authors.lastname: Tong
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Tung
authors.forename: Judyann
authors.initials: J
authors.lastname: Wiltsie
authors.forename: Dan
authors.initials: D
authors.lastname: Xie
authors.forename: Suoyu
authors.initials: S
authors.lastname: Xu
authors.forename: Jianying
authors.initials: J
authors.lastname: Xiao
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Hale
authors.forename: Shirly
authors.initials: S
authors.lastname: Pinto
authors.forename: Dong-Ming
authors.initials: DM
authors.lastname: Shen
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors*; D003500:Cyclization; D003517:Cyclopentanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009765:Obesity / Q000188:drug therapy
chemical_list: D000588:Amines; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D002268:Carboxypeptidases; C022448:lysosomal Pro-X carboxypeptidase