1-((S)-gamma-substituted prolyl)-(S)-2-cyanopyrrolidine as a novel series of highly potent DPP-IV inhibitors.
1-(Gamma-substituted prolyl)-(S)-2-cyanopyrrolidines were designed based on the predicted binding mode of the known DPP-IV inhibitor NVP-DPP728 and evaluated for their inhibitory activity. In structure-activity relationship study at the gamma-position of proline, it became clear that compounds bearing (S)-stereochemistry were 20-fold more potent than the antipode. Of these compounds, the (3,4-dicyanophenyl)amino- and (3-chloro-4-cyanophenyl)amino-derivatives showed the highest inhibitory activity.
Sakashita
Hiroshi
H
Pharmaceuticals Research Unit, Research & Development Division, Mitsubishi Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
Kitajima
Hiroshi
H
Nakamura
Mitsuharu
M
Akahoshi
Fumihiko
F
Hayashi
Yoshiharu
Y
D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects*; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D011480:Protease Inhibitors; D011759:Pyrrolidines; D018819:Dipeptidyl Peptidase 4