Inhibitors of dipeptidyl peptidase IV--recent advances and structural views.
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.
Hunziker
Daniel
D
Discovery Chemistry, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland. daniel.hunziker@roche.com
Hennig
Michael
M
Peters
Jens-Uwe
JU
D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects*; D018716:Molecular Mimicry; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D014961:X-Ray Diffraction
D011480:Protease Inhibitors; D018819:Dipeptidyl Peptidase 4