Design and synthesis of potent amido- and benzyl-substituted cis-3-amino-4-(2-cyanopyrrolidide)pyrrolidinyl DPP-IV inhibitors

J W Corbett; K Dirico; W Song; B P Boscoe; S D Doran; D Boyer; X Qiu; M Ammirati; M A Vanvolkenburg; R K McPherson; J C Parker; E D Cox

doi:10.1016/j.bmcl.2007.10.063

Design and synthesis of potent amido- and benzyl-substituted cis-3-amino-4-(2-cyanopyrrolidide)pyrrolidinyl DPP-IV inhibitors

Bioorg Med Chem Lett. 2007 Dec 15;17(24):6707-13. doi: 10.1016/j.bmcl.2007.10.063. Epub 2007 Oct 22.

Authors

J W Corbett¹, K Dirico, W Song, B P Boscoe, S D Doran, D Boyer, X Qiu, M Ammirati, M A Vanvolkenburg, R K McPherson, J C Parker, E D Cox

Affiliation

¹ Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.

PMID: 17977724
DOI: 10.1016/j.bmcl.2007.10.063

Abstract

The cis-3-amino-4-(2-cyanopyrrolidide)-pyrrolidine template has been shown to afford low nanomolar inhibitors of human DPP-IV that exhibit a robust PK/PD profile. An X-ray co-crystal structure of 5 confirmed the proposed mode of binding. The potent single digit DPP-IV inhibitor 53 exhibited a preferred PK/PD profile in preclinical animal models and was selected for additional profiling.

MeSH terms

Amination
Animals
Benzene / chemistry*
Cyanides / chemistry*
Dipeptidyl Peptidase 4 / chemistry
Dipeptidyl Peptidase 4 / metabolism
Dipeptidyl-Peptidase IV Inhibitors*
Dogs
Drug Design
Humans
Inhibitory Concentration 50
Models, Molecular
Molecular Structure
Protease Inhibitors / chemical synthesis*
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology*
Pyrroles / chemistry*
Pyrroles / pharmacology*
Rats
Stereoisomerism
Structure-Activity Relationship

Substances

Cyanides
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Pyrroles
DPP4 protein, human
Dipeptidyl Peptidase 4
Benzene