Inhibitors of Dipeptidyl Peptidase IV - Recent Advances and Structural Views

Authors: Hunziker, Daniel; Hennig, Michael; Peters, Jens-Uwe

Source: Current Topics in Medicinal Chemistry, Volume 5, Number 16, December 2005 , pp. 1623-1637(15)

Publisher: Bentham Science Publishers

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Abstract:

Prevalence of type 2 diabetes has increased dramatically in the last decades. Current medicines are not yet capable to efficiently prevent or reverse progression of the disease and its associated comorbidities. As a consequence, there is a great need for novel antidiabetic drugs. Treatments of type 2 diabetes that are based on enhanced and sustained action of insulinotropic incretin hormones such as GLP-1 have received much attention in the past years. Treatment strategies include administration of: 1) GLP-1 analogues that are resistant to degradation by the serine protease DPP-IV, and 2) small molecule DPP-IV inhibitors that are able to provide sustained action of endogenous GLP-1, again by preventing its degradation. This review summarizes recent research results for the second approach. It briefly touches upon the advantages that treatment of type 2 diabetes with DPP-IV inhibitors may offer over current medications. In the main section, several important structural classes of DPP-IV inhibitors are described and compared based on literature data. Specific attention is given to the analysis of several X-ray structures of enzyme-inhibitor co-crystals. Finally, as clinical data are steadily emerging for some of the most advanced development candidates, the last section of this review is providing a brief overview of some efficacy data from recent clinical studies with DPP-IV inhibitors.

Keywords: hypoglycemia; GLP-1; peptidomimetics; Cyanopyrrolidines; cyclization; monotherapy

Document Type: Research article

Affiliations: 1: F. Hoffmann-La Roche Ltd., Discovery Chemistry, PRBD-CM, Bldg. 92/1.76C, CH-4070 Basel, Switzerland.

Publication date: 2005-12-01