Current Topics in Medicinal Chemistry - Volume 7, Issue 6, 2007

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!

Type 2 diabetes is a chronic metabolic disease characterized by the presence of both fasting and postprandial hyperglycemia which is a result of pancreas β-cell dysfunction, deficiency in insulin secretion, insulin resistance and/or increased hepatic glucose production. More recently, the role of other glucoregulatory hormones, including glucagon, amylin, and the gut peptide glucagon-like peptide (GLP)-1, and an increase in the rate of postmeal carbohydrate absorption have also been included as important pathophysiologic defects. Existing anti-diabetes medications are often unefficient at achieving sustained glycemic control because they predominantly address only a single underlying defect. A number of alternative therapies for type 2 diabetes are currently under development that take advantage of the actions of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide on the pancreatic β-cell. One such approach is based on the inhibition of dipeptidyl peptidase IV (DPP-IV), the major enzyme responsible for degrading the incretins in vivo. DPP-IV exhibits characteristics that have allowed the development of specific inhibitors with proven efficacy in improving glucose tolerance in animal models of diabetes and type 2 diabetic patients. While enhancement of insulin secretion, resulting from blockade of incretin degradation, has been proposed to be the major mode of inhibitor action, there is also evidence that inhibition of gastric emptying, reduction in glucagon secretion, peripheral insulin sensitization and important effects on β-cell differentiation and survival can potentially preserve β-cell mass, and improve insulin secretory function and glucose handling in diabetic patients. The present article focuses on the preclinical and clinical data of DPP-IV inhibitors that make it unique therapeutic agents representing the next generation of antidiabetes drugs.

The emergence of glucagon-like peptide 1 (GLP-1) as a well validated approach to the treatment of type 2 diabetes and preclinical validation of dipeptidyl peptidase IV (DPP-4) inhibition as an alternate, oral approach to GLP-1 therapy prompted the initiation of a DPP-4 inhibitor program at Merck in 1999. DPP-4 inhibitors threo- and allo-isoleucyl thiazolidide were in-licensed to jump start the program; however, development was discontinued due to profound toxicity in rat and dog safety studies. The observation that both compounds inhibit the related proline peptidases DPP8 and DPP9 led to the hypothesis that inhibition of DPP8 and/or DPP9 could evoke severe toxicities in preclinical species. Indeed, the observed toxicities were recapitulated with a selective dual DPP8/9 inhibitor but not with an inhibitor selective for DPP-4. Thus, medicinal chemistry efforts focused on identifying a highly selective DPP-4 inibitor for clinical development. Initial work in an α-amino acid series related to isoleucyl thiazolidide was discontinued due to lack of selectivity; however, SAR studies on two screening leads led to the identification of a highly selective β-amino acid piperazine series. In an effort to stabilize the piperazine moiety, which was extensively metabolized in vivo, a series of bicyclic derivatives were prepared, culminating in the identification of a potent and selective triazolopiperazine series. Unlike their monocyclic counterparts, these analogs typically showed excellent pharmacokinetic properties in preclinical species. Optimization of this series led to the discovery of JANUVIA™ (sitagliptin), a highly selective DPP-4 inhibitor for the treatment of type 2 diabetes.

Xanthines and xanthine-like DPP-IV inhibitors were first disclosed in 2002. Since then, several dozen accounts of xanthine-based DPP-IV inhibitors have been published. Only a few presentations and journal articles have appeared, with the vast majority of information coming from the patent literature. DPP-IV inhibitors related to the xanthines include purine analogues with other arrangements of the nitrogen atoms in the core structure, imidazoles, uracils, pyrimidines, pyridines, and some fused pyridines. At least one compound derived from the xanthines has advanced into clinical trials, making it likely that these molecules will play a major role in the DPP-IV inhibition arena over the next several years.

Cyanopyrrolidines (cyanopyrrolidides, pyrrolidine-2-nitriles, prolinenitriles) as inhibitors of the serine protease dipeptidyl peptidase IV (DPP-IV, DP IV, CD26, EC 3.4.14.5) were first reported in 1995. The interest in this compound class grew immensely when DPP-IV was discovered as a target for the treatment of type 2 diabetes. The research on cyanopyrrolidines cumulated in the discoveries of vildagliptin (LAF237, NVP-LAF237) and saxagliptin (BMS-477118). These compounds entered Phase III clinical trials in 2004 and 2005, respectively, and an application for market approval has been filed for vildagliptin in 2006. Today cyanopyrrolidines are, as judged by the numbers of patent applications, the most prominent of several series of DPP-IV inhibitors, and have the potential to become valuable medicines for type 2 diabetes in the near future. This review summarizes some historical aspects of the discovery of cyanopyrrolidine DPP-IV inhibitors, and then focuses mainly on structure-activity-relationships, the evolution of different subseries, the possibilities to improve on the chemical instability that is associated with this compound class, and on the discoveries of vildagliptin and saxagliptin. Within this context, the properties of individual compounds and results from biological studies are discussed. The rationale of DPP-IV inhibition, clinical data, and the relevance of selectivity over related proteases are extensively reviewed in other contributions to this issue of Curr. Top. Med. Chem., and are therefore only very briefly touched..

The structure-activity relationships of azetidine-based DPP IV inhibitors will be discussed in detail in the following review. The azetidine-based DPP IV inhibitors can be divided into three main subtypes, the 2-cyanoazetidines, 3-fluoroazetidines and 2-ketoazetidines. These subtypes have been explored and structure-activity relationships have been established by several groups. Several compounds within each of these subtypes display sub micromolar potency against DPP IV. The most potent cyanoazetidines and ketoazetidines have large, hydrophobic amino acid groups bound to the azetidine nitrogen and display activities below 100nM. DPP IV inhibition is not sensitive to stereochemistry at the 2- position as both 2-(R)- and 2-(S)-cyano and -keto azetidines display similar inhibitory potencies. While these “warhead”- based cyano- and ketoazetidines have the potential for covalent, bond-forming inhibition, they can also react to internally cyclize into inactive ketopiperazines and dihydroketopyrazine. Thus, chemical instability was also explored for compounds in these two subtypes and certain members of the cyanoazetidine series display aqueous stability comparable to the closely related cyanopyrrolidines. Select 3-fluoroazetidines also display inhibitory potencies below 1μM without the propensity for cyclization and chemical instability associated with the other subseries.

The serine protease dipeptidyl peptidase IV (DPP-IV) is a clinically validated target for the treatment of type II diabetes and has received considerable interest from the pharmaceutical industry over the last years. Concomitant with a large variety of published small molecule DPP-IV inhibitors almost twenty co-crystal structures have been released to the public as of May 2006. In this review, we discuss the structural characteristics of the DPP-IV binding site and use the available X-ray information together with published structure-activity relationship data to identify the molecular interactions that are most important for tight enzyme-inhibitor binding. Optimized interactions with the two key recognition motifs, i.e. the lipophilic S1 pocket and the negatively charged Glu 205/206 pair, result in large gains in binding free energy, which can be further improved by additional favorable contacts to side chains that flank the active site. First examples show that the lessons learned from the Xray structures can be successfully incorporated into the design of novel DPP-IV inhibitors.

Dipeptidyl peptidase IV (DPP IV) is a validated target for the treatment of type 2 diabetes, with several inhibitors currently in phase 3 clinical trials. This review will mainly focus on proline-specific dipeptidyl peptidases related to DPP IV: fibroblast activation protein (FAP), dipeptidyl peptidase 8 (DPP8), dipeptidyl peptidase 9 (DPP9) and dipeptidyl peptidase II (DPP II). The biochemical and biological properties of these enzymes will be discussed, as well as the therapeutic potential of their inhibition. The development of potent and selective inhibitors for each of these peptidases will be described.

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