title: Discovery of aminoheterocycles as potent and brain penetrant prolylcarboxypeptidase inhibitors.
abstract: Efforts were dedicated to develop potent and brain penetrant prolylcarboxypeptidase (PrCP) inhibitors by replacing the amide group of original leads 1 and 2 with heterocycles. Aminopyrimidines including compound 32a were identified to display good PrCP inhibitory activity (32a, IC(50)=43 nM) and impressive ability to penetrate brain in mice (brain/plasma ratio: 1.4).
authors.affiliation: Department of Discovery Chemistry, Merck Research Laboratories, Rahway, NJ 07065-0900, USA. zhicai_wu@merck.com
authors.forename: Zhicai
authors.initials: Z
authors.lastname: Wu
authors.forename: Cangming
authors.initials: C
authors.lastname: Yang
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Graham
authors.forename: Andreas
authors.initials: A
authors.lastname: Verras
authors.forename: Renee M
authors.initials: RM
authors.lastname: Chabin
authors.forename: Suoyu
authors.initials: S
authors.lastname: Xu
authors.forename: Xinchun
authors.initials: X
authors.lastname: Tong
authors.forename: Dan
authors.initials: D
authors.lastname: Xie
authors.forename: Mike E
authors.initials: ME
authors.lastname: Lassman
authors.forename: Urmi R
authors.initials: UR
authors.lastname: Bhatt
authors.forename: Margarita M
authors.initials: MM
authors.lastname: Garcia-Calvo
authors.forename: Zhu
authors.initials: Z
authors.lastname: Shen
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.forename: Kelly
authors.initials: K
authors.lastname: Bleasby
authors.forename: Ranabir
authors.initials: R
authors.lastname: Sinharoy
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Hale
authors.forename: James R
authors.initials: JR
authors.lastname: Tata
authors.forename: Shirly
authors.initials: S
authors.lastname: Pinto
authors.forename: Steven L
authors.initials: SL
authors.lastname: Colletti
authors.forename: Dong-Ming
authors.initials: DM
authors.lastname: Shen
mesh_terms: D000577:Amides / Q000737:chemistry; D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors*; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000588:Amines; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D002268:Carboxypeptidases; C022448:lysosomal Pro-X carboxypeptidase