ABSTRACT
Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment of type 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolidide warhead led to the discovery of potent inhibitors of DPP-IV that lack activity against DPP8 and DPP9. Further modification led to an extremely potent (Ki(DPP)(-)(IV) = 1.0 nM) and selective (Ki(DPP8) > 30 microM; Ki(DPP9) > 30 microM) clinical candidate, ABT-279, that is orally available, efficacious, and remarkably safe in preclinical safety studies.
Subject(s)
Adenosine Deaminase Inhibitors , Dipeptidyl-Peptidase IV Inhibitors , Glycoproteins/antagonists & inhibitors , Hypoglycemic Agents/chemical synthesis , Pyridines/chemical synthesis , Pyrrolidines/chemical synthesis , Adenosine Deaminase/chemistry , Administration, Oral , Animals , Binding Sites , Caco-2 Cells , Crystallography, X-Ray , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl Peptidase 4/chemistry , Dogs , Female , Glucose Intolerance/drug therapy , Glycoproteins/chemistry , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Macaca fascicularis , Models, Molecular , Molecular Structure , Pyridines/pharmacokinetics , Pyridines/pharmacology , Pyrrolidines/pharmacokinetics , Pyrrolidines/pharmacology , Rats , Rats, Sprague-Dawley , Rats, Zucker , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of (5-substituted pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidine (C5-Pro-Pro) analogues was discovered as dipeptidyl peptidase IV (DPPIV) inhibitors as a potential treatment of diabetes and obesity. X-ray crystallography data show that these inhibitors bind to the catalytic site of DPPIV with the cyano group forming a covalent bond with the serine residue of DPPIV. The C5-substituents make various interactions with the enzyme and affect potency, chemical stability, selectivity, and PK properties of the inhibitors. Optimized analogues are extremely potent with subnanomolar K(i)'s, are chemically stable, show very little potency decrease in the presence of plasma, and exhibit more than 1,000-fold selectivity against related peptidases. The best compounds also possess good PK and are efficacious in lowering blood glucose in an oral glucose tolerance test in ZDF rats.
