title: Discovery and optimization of orally active cyclohexane-based prolylcarboxypeptidase (PrCP) inhibitors.
abstract: The synthesis, SAR, binding affinities and pharmacokinetic profiles are described for a series of cyclohexane-based prolylcarboxypeptidase (PrCP) inhibitors discovered by high throughput screening. Compounds show high levels of ex vivo target engagement in mouse plasma 20 h post oral dose.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA. Electronic address: john_debenham@merck.com.
authors.forename: John S
authors.initials: JS
authors.lastname: Debenham
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Graham
authors.forename: Andreas
authors.initials: A
authors.lastname: Verras
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Clements
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Kuethe
authors.forename: Christina
authors.initials: C
authors.lastname: Madsen-Duggan
authors.forename: Wensheng
authors.initials: W
authors.lastname: Liu
authors.forename: Urmi R
authors.initials: UR
authors.lastname: Bhatt
authors.forename: Dunlu
authors.initials: D
authors.lastname: Chen
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: Huaibing
authors.initials: H
authors.lastname: He
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Li
authors.forename: JeanMarie
authors.initials: J
authors.lastname: Lisnock
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: 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; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors*; D003510:Cyclohexanes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009765:Obesity / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: D003510:Cyclohexanes; D004791:Enzyme Inhibitors; D002268:Carboxypeptidases; C022448:lysosomal Pro-X carboxypeptidase
keywords: Inhibitor; Obesity; PrCP; Prolylcarboxypeptidase; Serine protease