title: Discovery of benzimidazole pyrrolidinyl amides as prolylcarboxypeptidase inhibitors.
abstract: A series of benzimidazole pyrrolidinyl amides containing a piperidinyl group were discovered as novel prolylcarboxypeptidase (PrCP) inhibitors. Low-nanomolar IC(50)'s were achieved for several analogs, of which compound 9b displayed modest ex vivo target engagement in eDIO mouse plasma. Compound 9b was also studied in vivo for its effect on weight loss and food intake in an eDIO mouse model and the results will be discussed.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065-0900, USA. hong_shen@merck.com
authors.forename: Hong C
authors.initials: HC
authors.lastname: Shen
authors.forename: Fa-Xiang
authors.initials: FX
authors.lastname: Ding
authors.forename: Changyou
authors.initials: C
authors.lastname: Zhou
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Xiong
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: Michael 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: Dunlu
authors.initials: D
authors.lastname: Chen
authors.forename: Ranabir
authors.initials: R
authors.lastname: Sinharoy
authors.forename: Jeffery 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: Dong-Ming
authors.initials: DM
authors.lastname: Shen
authors.forename: Steven L
authors.initials: SL
authors.lastname: Colletti
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D002268:Carboxypeptidases; C022448:lysosomal Pro-X carboxypeptidase