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cis -2,5-Dicyanopyrrolidine Inhibitors of Dipeptidyl Peptidase IV: Synthesis and in Vitro, in Vivo, and X-ray Crystallographic Characterization

2006; American Chemical Society; Volume: 49; Issue: 11 Linguagem: Inglês

10.1021/jm0600085

1520-4804

Stephen W. Wright, Mark Ammirati, Kim Andrews, Anne M. Brodeur, Dennis E. Danley, Shawn D. Doran, Jay S. Lillquist, Lester D. McClure, R. Kirk McPherson, Stephen Orena, Janice C. Parker, Jana Polívková, Xiayang Qiu, Walter C. Soeller, Carolyn B. Soglia, Judith L. Treadway, Maria A. VanVolkenburg, Hong Wang, Donald C. Wilder, Thanh V. Olson,

Neuropeptides and Animal Physiology

Inhibitors of the glucagon-like peptide-1 (GLP-1) degrading enzyme dipeptidyl peptidase IV (DPP-IV) have been shown to be effective treatments for type 2 diabetes in animal models and in human subjects. A novel series of cis-2,5-dicyanopyrrolidine alpha-amino amides were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. 1-({[1-(Hydroxymethyl)cyclopentyl]amino}acetyl)pyrrolidine-2,5-cis-dicarbonitrile (1c) is an achiral, slow-binding (time-dependent) inhibitor of DPP-IV that is selective for DPP-IV over other DPP isozymes and proline specific serine proteases, and which has oral bioavailability in preclinical species and in vivo efficacy in animal models. The mode of binding of the cis-2,5-dicyanopyrrolidine moiety was determined by X-ray crystallography. The hydrochloride salt of 1c was further profiled for development as a potential new treatment for type 2 diabetes.