Discovery of long-acting N-(cyanomethyl)-N-alkyl-L-prolinamide inhibitors of dipeptidyl peptidase IV.
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.
Kondo
Takashi
T
Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan. t.kondou@ono.co.jp
Nekado
Takahiro
T
Sugimoto
Isamu
I
Ochi
Kenya
K
Takai
Shigeyuki
S
Kinoshita
Atsushi
A
Hatayama
Akira
A
Yamamoto
Susumu
S
Kawabata
Kazuhito
K
Nakai
Hisao
H
Toda
Masaaki
M
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
D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors; D011392:Proline; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; C056291:prolinamide