Synthesis, SAR, and atropisomerism of imidazolopyrimidine DPP4 inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 21; pp. 6273 - 6276
• Main Authors: O’Connor, Stephen P., Wang, Ying, Simpkins, Ligaya M., Brigance, Robert P., Meng, Wei, Wang, Aiying, Kirby, Mark S., Weigelt, Carolyn A., Hamann, Lawrence G.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.11.2010; Elsevier
• Subjects: Atropisomerism; Biological and medical sciences; Catalytic Domain; Dipeptidases - antagonists & inhibitors; Dipeptidyl peptidase 4; Dipeptidyl-Peptidase IV Inhibitors - chemical synthesis; Dipeptidyl-Peptidase IV Inhibitors - chemistry; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - antagonists & inhibitors; DPP4; General and cellular metabolism. Vitamins; Imidazoles - chemical synthesis; Imidazoles - pharmacology; Indicators and Reagents; Isomerism; Kinetics; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Pyrimidines - chemical synthesis; Pyrimidines - pharmacology; Solvents; Structure-Activity Relationship; DPP4; Atropisomerism; Dipeptidyl peptidase 4; Dipeptidyl-peptidase IV; Enzyme; Angular nitrogen heterocycle; Benzene derivatives; Enzyme inhibitor; Inhibitor enzyme complex; In vitro; Modeling; Peptidases; Atropoisomerism; Chlorine Organic compounds; Enantiomer; Molecular model; Bicyclic compound; Hydrolases; Dipeptidyl-peptidase IV inhibitor; Chemical synthesis; Primary amine
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.08.090

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. 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.