title: Discovery of benzodihydroisofurans as novel, potent, bioavailable and brain-penetrant prolylcarboxypeptidase inhibitors.
abstract: A series of benzodihydroisofurans were discovered as novel, potent, bioavailable and brain-penetrant prolylcarboxypeptidase (PrCP) inhibitors. The structure-activity relationship (SAR) is focused on improving PrCP activity and metabolic stability, and reducing plasma protein binding. In the established diet-induced obese (eDIO) mouse model, compound ent-3a displayed target engagement both in plasma and in brain. However, this compound failed to induce significant body weight loss in eDIO mice in a five-day study.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065-0900, USA. hongshen@stanfordalumni.org
authors.forename: Hong C
authors.initials: HC
authors.lastname: Shen
authors.forename: Fa-Xiang
authors.initials: FX
authors.lastname: Ding
authors.forename: Jinlong
authors.initials: J
authors.lastname: Jiang
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: Qing
authors.initials: Q
authors.lastname: Chen
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: Wayne
authors.initials: W
authors.lastname: Geissler
authors.forename: Zhu
authors.initials: Z
authors.lastname: Shen
authors.forename: Beth Ann
authors.initials: BA
authors.lastname: Murphy
authors.forename: Judith N
authors.initials: JN
authors.lastname: Gorski
authors.forename: Judyann
authors.initials: J
authors.lastname: Wiltsie
authors.forename: Ranabir
authors.initials: R
authors.lastname: SinhaRoy
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*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D055808:Drug Discovery; D004355:Drug Stability; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008820:Mice, Obese; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D005663:Furans; D002268:Carboxypeptidases; C022448:lysosomal Pro-X carboxypeptidase