1-((S)-gamma-substituted prolyl)-(S)-2-cyanopyrrolidine as a novel series of highly potent DPP-IV inhibitors

Hiroshi Sakashita; Hiroshi Kitajima; Mitsuharu Nakamura; Fumihiko Akahoshi; Yoshiharu Hayashi

doi:10.1016/j.bmcl.2005.03.077

1-((S)-gamma-substituted prolyl)-(S)-2-cyanopyrrolidine as a novel series of highly potent DPP-IV inhibitors

Bioorg Med Chem Lett. 2005 May 16;15(10):2441-5. doi: 10.1016/j.bmcl.2005.03.077.

Authors

Hiroshi Sakashita¹, Hiroshi Kitajima, Mitsuharu Nakamura, Fumihiko Akahoshi, Yoshiharu Hayashi

Affiliation

¹ Pharmaceuticals Research Unit, Research & Development Division, Mitsubishi Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.

PMID: 15863294
DOI: 10.1016/j.bmcl.2005.03.077

Abstract

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.

MeSH terms

Dipeptidyl Peptidase 4 / drug effects*
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology*
Pyrrolidines / chemistry
Pyrrolidines / pharmacology*
Stereoisomerism
Structure-Activity Relationship

Substances

Protease Inhibitors
Pyrrolidines
Dipeptidyl Peptidase 4