title: Discovery of long-acting N-(cyanomethyl)-N-alkyl-L-prolinamide inhibitors of dipeptidyl peptidase IV.
abstract: Details of structure-activity relationships (SAR) for P2 moiety of a P1 2-cyanopyrrolidine dipeptidyl peptidase IV (DPP-IV) inhibitor 4a including stereochemistry are presented. Based on this information, a series of P1 (N-alkyl)aminoacetonitrile analogs 9-20 possessing optimal P2 structure were synthesized and evaluated as inhibitors of DPP-IV. Among them, a representative compound 11, N-(cyanomethyl)-N-ethyl-L-prolinamide, was further evaluated to determine its effect on the plasma glucose level. Also 4a, 10, and 11 were evaluated for their isozyme selectivity to predict their safety problems.
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan. t.kondou@ono.co.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Kondo
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nekado
authors.forename: Isamu
authors.initials: I
authors.lastname: Sugimoto
authors.forename: Kenya
authors.initials: K
authors.lastname: Ochi
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Takai
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kinoshita
authors.forename: Akira
authors.initials: A
authors.lastname: Hatayama
authors.forename: Susumu
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Kawabata
authors.forename: Hisao
authors.initials: H
authors.lastname: Nakai
authors.forename: Masaaki
authors.initials: M
authors.lastname: Toda
mesh_terms: D001786:Blood Glucose / Q000187:drug effects; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry; D006801:Humans; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors; D011392:Proline; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; C056291:prolinamide