Dipeptidyl Peptidase-4 Inhibitors For The Treatment Of Type 2 Diabetes Mellitus

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Diabetes is a fast-growing, global chronic metabolic disorder. According to the newest data from the International Diabetes Federation (IDF), about 425 million adults had diabetes in 2017, and the number is expected to rise to 700 million in 2045. DPP-4 (CD26, EC 3.4.14.5) is a serine peptidase expressed as a 220 kDa homodimeric type II transmembrane glycoprotein on the surface of various cell types.

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The mechanisms for the glucose-lowering action of DPP-4 inhibitors include GLP-1-dependent and GLP-1-independent mechanisms. Apart from GLP-1, other four possible bioactive peptides might be GIP, oxyntomodulin, pituitary adenylate cyclase-activating peptide, and stromal cell-derived factor-1α. Still, the exact GLP-1–independent mechanisms remain to be fully understood.

Figure 1: Mechanisms for the glucose-lowering action of DPP-4 inhibitors

The idea of inhibiting DPP-4 was suggested as a potential new therapy for T2DM 20 years ago. It became available in 2006. Currently, there are at least 12 DPP-4 inhibitors that have already been approved for the market. Sitagliptin was the first DPP-4 inhibitor, granted by FDA, followed by vildagliptin, saxagliptin, alogliptin, and linagliptin. New members continue to be approved: anagliptin, gemigliptin, teneligliptin in 2012; evogliptin, omarigliptin, and trelagliptin in 2015, and gosogliptin in 2016.

Figure 2: Marketed DPP-4 inhibitors

The development of synthetic and natural DPP-4 inhibitors from 2012 to 2017 was reviewed. Synthetic DPP-4 inhibitors mainly include the peptidomimetic series and the non-peptidomimetic DPP-4 inhibitors. The peptidomimetic series have synthesized and evaluated for their DPP-4 inhibitory activity, including the α-series and the β series. Xanthine analogs, pyrimidinone analogs, phenethylamine/phenpropylamine derivatives, arylmethylamine analogs, and other non-peptidomimetic DPP-4 inhibitors also showed remarkable DPP-4 inhibitory activity.

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This article reviewed fifty-three synthetic compounds responsible for the DPP-4 inhibitory activity of which eight synthetic compounds exhibited the potent DPP-4 inhibitory with the IC50 value below 1 nM (34, 29, 10, 44, 28, 19, 26 and 47). However, compound 34 was not suitable to be further studied as a potential once-weekly inhibitor due to the discontented preclinical pharmacokinetic profile. The others might be studied as candidates of potential DPP-4 inhibitors. Apart from synthetic compounds, twenty-seven natural compounds and peptides released from dairy ingredients were also summarized for identifying potential DPP-4 inhibitors. Only compound 66 showed the strongest inhibitory activity with the IC50 value below 1 nM. Their physico-chemical properties, biological activities against DPP-4, selectivity against DPP-8/9 were also discussed.

In addition, the active site of DPP-4 was also reviewed. The large cavity of DPP-4 (diameter ≥ 20 Å) formed between the α/β-hydrolase domain and an eight-bladed β-propeller domain made it possible to accept inhibitors of various shapes. By Reviewing literatures it is concluded that the binding pocket of DPP-4 involves S1 pocket (formed by Ser630, Tyr631, Val656, Trp659, Tyr662, Tyr666, Asn710, Val711 and His740), S2 pocket (containing the active triad Glu205 and Glu206, Ser209, Phe357, Arg358 and Arg125), catalytic triad Val207, Lys544, Tyr547, Trp627, Trp629, Asp708 and other residues, of which S2 pocket is associated with selectivity of DPP-4 inhibitors.

The SARs analysis of potent DPP-4 inhibitors indicated that pyrrolidine, aminopiperidine, xanthine, carbonyl, cyanobenzyl, and other groups were crucial for inhibitory activity. The aromatic ring core (such as pyrimidine, benzimidazole, quinoline, isoquinoline, pyridine, benzene, etc) provides π-π interaction with Arg125. In addition, the xanthine core forms hydrogen bonds with Tyr630 and π-π interaction with Tyr547. Benzene ring, cyanobenzyl, butynyl, or other small cyclic substituent is necessary since it occupies S1 pocket with hydrophobic interaction with Ser630/His740. In particular, aminopiperidine or piperazine is crucial for DPP-4 inhibitory activity, which forms a salt bridge with Glu205, Glu206 or Tyr662 in the S2 pocket.

Figure 3: Key interactions and binding models of DPP-4 inhibitors

In summary, DPP-4 is a promising target for the treatment of type 2 diabetes mellitus (T2DM). This review might be useful for molecular designing and will significantly promote the development of potent DPP-4 inhibitors as T2DM drugs.

These findings are described in the article entitled Recent progress of the development of dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus, recently published in the European Journal of Medicinal Chemistry. This work was conducted by Ning Li, Li-Jun Wang, Bo Jiang, Xiang-qian Li, Chuan-long Guo, Shu-ju Guo, Da-Yong Shi from the Chinese Academy of Sciences.

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Cite this article as:
Da-Yong Shi. Dipeptidyl Peptidase-4 Inhibitors For The Treatment Of Type 2 Diabetes Mellitus, Science Trends, 2018. Available at:
http://doi.org/10.31988/SciTrends.19730
*Note, DOIs are registered Friday weekly and therefore may not work until then.

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