1-(3-Hydroxy-1-adamantyl)aminoacetyl-2-cyano-(S)-pyrrolidine: A Potent, Selective, and Orally Bioavailable Dipeptidyl Peptidase IV Inhibitor with Antihyperglycemic Properties

摘要

Dipeptidyl peptidase IV (DPP-IV) inhibition has the potential to become a valuable therapy for type 2 diabetes. The synthesis and structure-activity relationship of a new DPP-IV inhibitor class, N-substituted-glycyl-2-cyanopyrrolidines, are described as well as the path that led from clinical development compound 1-2-5-cyanopyridin-2-ylaminoethylaminoacetyl-2-cyano-(S)-pyrrolidine (NVP-DPP728, 8c) to its follow-up, 1-3-hydroxy-1-adamantyl)aminoacetyl-2-cyano-(S)-pyrrolidine (NVP-LAF237, 12j). The pharmacological profile of 12j in obese Zucker fa/fa rats along with pharmacokinetic profile comparison of 8c and 12j in normal cynomolgus monkeys is discussed. The results suggest that 12j is a potent, stable, selective DPP-IV inhibitor possessing excellent oral bioavailability and potent antihyperglycemic activity with potential for once-a-day administration.