ABSTRACT
A series of (4beta-substituted)-L-prolylpyrrolidine analogs lacking the electrophilic nitrile function were synthesized and their dipeptidyl peptidase IV (DPP-IV) inhibitory activity and duration of ex vivo activity were evaluated. Structural optimization of a N-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine analog 8, which was found by high-speed analog synthesis, was carried out to improve the potency and duration of action. A representative compound 26 was evaluated to assess its effect on the plasma glucose level after the oGTT (oral glucose tolerance test) in normal rats. Structure-activity relationships (SAR) are also presented.
Subject(s)
Blood Glucose/drug effects , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Pyrrolidines/chemical synthesis , Animals , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Drug Design , Glucose Tolerance Test , Nitriles , Pyrrolidines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Details of structure-activity relationships (SAR) for P2 moiety of a P1 2-cyanopyrrolidine dipeptidyl peptidase IV (DPP-IV) inhibitor 4a including stereochemistry are presented. Based on this information, a series of P1 (N-alkyl)aminoacetonitrile analogs 9-20 possessing optimal P2 structure were synthesized and evaluated as inhibitors of DPP-IV. Among them, a representative compound 11, N-(cyanomethyl)-N-ethyl-L-prolinamide, was further evaluated to determine its effect on the plasma glucose level. Also 4a, 10, and 11 were evaluated for their isozyme selectivity to predict their safety problems.