title: The discovery of non-benzimidazole and brain-penetrant prolylcarboxypeptidase inhibitors.
abstract: Novel prolylcarboxypeptidase (PrCP) inhibitors with nanomolar IC(50) values were prepared by replacing the previously described dichlorobenzimidazole-substituted pyrrolidine amides with a variety of substituted benzylamine amides. In contrast to prior series, the compounds demonstrated minimal inhibition shift in whole serum and minimal recognition by P-glycoprotein (P-gp) efflux transporters. The compounds were also cell permeable and demonstrated in vivo brain exposure. The in vivo effect of compound (S)-6e on weight loss in an established diet-induced obesity (eDIO) mouse model was studied.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA. thomas.graham@merck.com
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Graham
authors.forename: Hong C
authors.initials: HC
authors.lastname: Shen
authors.forename: Wensheng
authors.initials: W
authors.lastname: Liu
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Xiong
authors.forename: Andreas
authors.initials: A
authors.lastname: Verras
authors.forename: Kelly
authors.initials: K
authors.lastname: Bleasby
authors.forename: Urmi R
authors.initials: UR
authors.lastname: Bhatt
authors.forename: Renee M
authors.initials: RM
authors.lastname: Chabin
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: Michael E
authors.initials: ME
authors.lastname: Lassman
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: Dan
authors.initials: D
authors.lastname: Xie
authors.forename: Suoyu
authors.initials: S
authors.lastname: Xu
authors.forename: Steven L
authors.initials: SL
authors.lastname: Colletti
authors.forename: James R
authors.initials: JR
authors.lastname: Tata
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: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000577:Amides / Q000737:chemistry; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001692:Biological Transport; D001835:Body Weight; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008956:Models, Chemical; D009765:Obesity / Q000188:drug therapy; D011759:Pyrrolidines / Q000737:chemistry; D013997:Time Factors
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000577:Amides; D001562:Benzimidazoles; D011759:Pyrrolidines; C095122:multidrug resistance protein 3; D002268:Carboxypeptidases; C022448:lysosomal Pro-X carboxypeptidase; C032519:pyrrolidine