Editorial [ Hot Topic: DPP-IV as a Target in Medicinal Chemistry and Drug Discovery (Guest Editor: Dr. Jens-Uwe Peters) ]

The serine protease DPP-IV (dipeptidyl peptidase IV, DP IV) has been a subject of research since its discovery in 1967. The role of this enzyme in glucose homeostasis was elucidated in the 1990s, and DPP-IV inhibition was recognized as a potential treatment of type 2 diabetes with anticipated advantages over established therapies. This led to an immense increase in research, and has made this enzyme one of the most popular therapeutic targets of the last ten years. In April 2006, five DPP-IV inhibitors had reached phase III clinical trials, and New Drug Applications had been filed for two of them. Today, we can hope to have DPP-IV inhibitors available as novel treatments for type 2 diabetes in the near future. This issue aims to document the discoveries of some of these new medicines, and the current status of research. The issue is opened by Elena Sebokova, Andreas D. Christ, Markus Bohringer and Jacques Mizrahi, who give an introduction to the biological background of DPP-IV and the incretin system, and summarise the current knowledge on DPP-IV as a target for type 2 diabetes. The authors interpret salient preclinical results and clinical studies and discuss why DPP-IV inhibitors have the potential to become the next generation of antidiabetic drugs The next reviews focus on some of the most prominent series of DPP-IV inhibitors. In their story of the β-phenethylamines, Nancy A. Thornberry and Ann E. Weber give an account of the research that led to the discovery of one of the most advanced DPP-IV inhibitors, sitagliptin. This case study is full of elegant solutions to a variety of encountered issues and will certainly become a classic! Bruce Szczepankiewicz and Ravi Kurukulasuriya give an insightful overview on the xanthine-type DPP-IV inhibitors. The xanthines are a diverse class of inhibitors and have so far been described mainly in patent literature. A xanthine-derived compound, SYR322, is currently undergoing phase III clinical trials. This is followed by a review on another popular compound class, the cyanopyrrolidines. The evolution of different subseries, which cumulated in the discoveries of vildagliptin and saxagliptin, is described. These reviews on major series of DPP-IV inhibitors are complemented by highlighting a particular series in the wide field of peptide-like inhibitors, the azetidines. A team of authors around Dana Ferraris, who has been a key player in the exploration of the azetidines, introduces us to the details of this compound class. X-ray crystal structures have revealed that all these inhibitors share common key interactions in their recognition by DPPIV. Bernd Kuhn, Michael Hennig, and Patrizio Mattei review the molecular recognition by DPP-IV in detail. The authors combine structural information with published SAR data to explain the characteristics of DPP-IV's recognition sites, and discuss possibilities for structure-based design and virtual screening. Throughout this issue, DPP-IV related enzymes like FAP, DPP8, DPP9, and DPP-II are repeatingly mentioned. These “DASH proteins” are reviewed in a final contribution to this issue by Pieter Van der Veken, Achiel Haemers, and Koen Augustyns. The function and significance of these enzymes, as well as their properties and the SAR of their inhibitors, are extensively discussed. Interestingly, some of these enzymes are promising therapeutic targets on their own. Thanks to all authors, this issue has become a collection of inspiring contributions to a range of DPP-IV related topics. Hopefully anyone engaged in the field of DPP-IV, antidiabetics, proteases, or with an interest in drug discovery in general, will enjoy it!