title: A new class of prolylcarboxypeptidase inhibitors, part 1: discovery and evaluation.
abstract: 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 IC(50) 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.
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: Iyassu K
authors.initials: IK
authors.lastname: Sebhat
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Xiong
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: Jianying
authors.initials: J
authors.lastname: Xiao
authors.forename: Dan
authors.initials: D
authors.lastname: Xie
authors.forename: Suoyu
authors.initials: S
authors.lastname: Xu
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: D000818:Animals; D000440:Butanols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors*; 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; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000440:Butanols; D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D002268:Carboxypeptidases; C022448:lysosomal Pro-X carboxypeptidase; C032519:pyrrolidine