Discovery, Structure−Activity Relationship, and Pharmacological Evaluation of
(5-Substituted-pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidines as Potent Dipeptidyl Peptidase IV
Inhibitors
posted on 2006-06-15, 00:00authored byZhonghua Pei, Xiaofeng Li, Kenton Longenecker, Thomas W. von Geldern, Paul E. Wiedeman, Thomas H. Lubben, Bradley A. Zinker, Kent Stewart, Stephen J. Ballaron, Michael A. Stashko, Amanda K. Mika, David W. A. Beno, Michelle Long, Heidi Wells, Anita J. Kempf-Grote, David J. Madar, Todd S. McDermott, Lakshmi Bhagavatula, Michael G. Fickes, Daisy Pireh, Larry R. Solomon, Marc R. Lake, Rohinton Edalji, Elizabeth H. Fry, Hing L. Sham, James M. Trevillyan
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 Ki'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.