| Abstract
| - A series of (5-substituted pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidine (C5-Pro-Pro) analogues was discoveredas dipeptidyl peptidase IV (DPPIV) inhibitors as a potential treatment of diabetes and obesity. X-raycrystallography data show that these inhibitors bind to the catalytic site of DPPIV with the cyano groupforming a covalent bond with the serine residue of DPPIV. The C5-substituents make various interactionswith the enzyme and affect potency, chemical stability, selectivity, and PK properties of the inhibitors.Optimized analogues are extremely potent with subnanomolar Ki's, are chemically stable, show very littlepotency decrease in the presence of plasma, and exhibit more than 1,000-fold selectivity against relatedpeptidases. The best compounds also possess good PK and are efficacious in lowering blood glucose in anoral glucose tolerance test in ZDF rats.
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