ABSTRACT
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-yl)amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidine (NVP-DPP728, 8c) to its follow-up, 1-[[(3-hydroxy-1-adamantyl) amino]acetyl]-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.
Subject(s)
Adamantane/chemical synthesis , Dipeptidyl Peptidase 4/metabolism , Enzyme Inhibitors/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Pyrrolidines/chemical synthesis , Adamantane/analogs & derivatives , Adamantane/chemistry , Adamantane/pharmacology , Administration, Oral , Animals , Biological Availability , Blood Glucose/analysis , Caco-2 Cells , Crystallography, X-Ray , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Macaca fascicularis , Male , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Rats , Rats, Zucker , Structure-Activity RelationshipABSTRACT
Dipeptidyl peptidase IV (DPP-IV) inhibition has the potential to become a valuable therapy for type 2 diabetes. We report the first use of solid-phase synthesis in the discovery of a new DPP-IV inhibitor class and a solution-phase synthesis that is practical up to the multikilogram scale. One compound, NVP-DPP728 (2), is profiled as a potent, selective, and short-acting DPP-IV inhibitor that has excellent oral bioavailability and potent antihyperglycemic activity.
