Synthesis, SAR, and atropisomerism of imidazolopyrimidine DPP4 inhibitors

Stephen P O'Connor; Ying Wang; Ligaya M Simpkins; Robert P Brigance; Wei Meng; Aiying Wang; Mark S Kirby; Carolyn A Weigelt; Lawrence G Hamann

doi:10.1016/j.bmcl.2010.08.090

Synthesis, SAR, and atropisomerism of imidazolopyrimidine DPP4 inhibitors

Bioorg Med Chem Lett. 2010 Nov 1;20(21):6273-6. doi: 10.1016/j.bmcl.2010.08.090. Epub 2010 Aug 22.

Authors

Stephen P O'Connor¹, Ying Wang, Ligaya M Simpkins, Robert P Brigance, Wei Meng, Aiying Wang, Mark S Kirby, Carolyn A Weigelt, Lawrence G Hamann

Affiliation

¹ Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08543-5400, USA. steve.oconnor@bms.com

PMID: 20833042
DOI: 10.1016/j.bmcl.2010.08.090

Abstract

The synthesis and SAR of aminomethyl-substituted imidazolopyrimidine DPP4 inhibitors bearing varied pendant aryl groups is described. Compound 1, which exists as a separable mixture of non-interconvertible atropisomers was used as the starting point for investigation. The effects of substituent pattern and type as well as stereochemical effects on inhibitor potency are discussed.

MeSH terms

Catalytic Domain
Dipeptidases / antagonists & inhibitors
Dipeptidyl-Peptidase IV Inhibitors / chemical synthesis*
Dipeptidyl-Peptidase IV Inhibitors / chemistry
Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / antagonists & inhibitors
Imidazoles / chemical synthesis*
Imidazoles / pharmacology*
Indicators and Reagents
Isomerism
Kinetics
Models, Molecular
Pyrimidines / chemical synthesis*
Pyrimidines / pharmacology*
Solvents
Structure-Activity Relationship

Substances

Dipeptidyl-Peptidase IV Inhibitors
Imidazoles
Indicators and Reagents
Pyrimidines
Solvents
Dipeptidases
DPP9 protein, human
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
DPP8 protein, human