A Review of Dipeptidyl Peptidase-4 (DPP-4) and its potential synthetic derivatives in the management of Diabetes Mellitus
Mohd. Javed Naim 1
Journal of Angiotherapy 8(1) 1-12 https://doi.org/10.25163/angiotherapy.819417
Submitted: 03 December 2023 Revised: 18 December 2023 Published: 08 January 2024
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors are a type of oral medication used to treat type 2 diabetes mellitus (T2DM). They have become increasingly popular due to their effectiveness and safety in managing the condition. DPP-4 inhibitors function by inhibiting the enzyme that breaks down the incretin hormones, namely glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). These medicines efficiently raise the levels of active GLP-1 and GIP by blocking DPP-4 activity. As a result, there is an increase in the production of insulin, a decrease in the release of glucagon, and a lowering of glucose levels after a meal. Multiple clinical trials have conclusively shown that DPP-4 inhibitors effectively lower glycated hemoglobin (HbA1c) levels. Certain studies have even proved their equivalent efficacy to other anti-diabetic medications such as metformin or sulfonylureas. Furthermore, DPP-4 inhibitors possess the benefit of being weight-neutral and exhibiting a little risk of hypoglycemia. These qualities render them a compelling option for patients with type 2 diabetes mellitus who are overweight or susceptible to hypoglycemia episodes. In general, DPP-4 inhibitors are a promising therapeutic choice for the management of type 2 diabetes mellitus (T2DM), offering effective regulation of blood sugar levels with a minimal likelihood of adverse effects. Nevertheless, it is important to acknowledge some restrictions and factors to take into account, including the possibility of heightened susceptibility to pancreatitis, nasopharyngitis, and certain drug-drug combinations. Additional investigation is necessary to completely clarify the long-term safety and potential supplementary advantages of DPP-4 inhibitors.
Keywords: DPP-4, Diphenyl peptidase-4 inhibitors, Diabetes mellitus, Type II diabetes, GLP-1.
References
Abd El-Karim, S. S., Anwar, M. M., Syam, Y. M., Nael, M. A., Ali, H. F., & Motaleb, M. A. (2018). Rational design and synthesis of new tetralin-sulfonamide derivatives as potent anti-diabetics and DPP-4 inhibitors: 2D & 3D QSAR, in vivo radiolabeling and bio distribution studies. Bioorganic chemistry, 81, 481-493.
Ahrén, B. (2005). Inhibition of dipeptidyl peptidase-4 (DPP-4)-a novel approach to treat type 2 diabetes. Current Enzyme Inhibition, 1(1), 65-73.
Ahrén, B. (2019). DPP-4 inhibition and the path to clinical proof. Frontiers in endocrinology, 10, 376.
Andukuri, R., Drincic, A., & Rendell, M. (2009). Alogliptin: a new addition to the class of DPP-4 inhibitors. Diabetes, metabolic syndrome and obesity: targets and therapy, 117-126.
Baetta, R., & Corsini, A. (2011). Pharmacology of dipeptidyl peptidase-4 inhibitors: similarities and differences. Drugs, 71, 1441-1467.
Bindu, B., Vijayalakshmi, S., & Manikandan, A. (2020). Synthesis and discovery of triazolo-pyridazine-6-yl-substituted piperazines as effective anti-diabetic drugs; evaluated over dipeptidyl peptidase-4 inhibition mechanism and insulinotropic activities. European Journal of Medicinal Chemistry, 187, 111912.
Ceriello, A., Sportiello, L., Rafaniello, C., & Rossi, F. (2014). DPP-4 inhibitors: pharmacological differences and their clinical implications. Expert opinion on drug safety, 13(sup1), 57-68.
Cho, Y. K., Kang, Y. M., Lee, S. E., Lee, J., Park, J. Y., Lee, W. J., ... & Jung, C. H. (2018). Efficacy and safety of combination therapy with SGLT2 and DPP4 inhibitors in the treatment of type 2 diabetes: A systematic review and meta-analysis. Diabetes & metabolism, 44(5), 393-401.
Dastjerdi, H. F., Naderi, N., Nematpour, M., Rezaee, E., Mahboubi-Rabbani, M., Ebrahimi, M., ... & Tabatabai, S. A. (2020). Design, synthesis and anti-diabetic activity of novel 1, 2, 3-triazole-5-carboximidamide derivatives as dipeptidyl peptidase-4 inhibitors. Journal of Molecular Structure, 1221, 128745.
Deacon, C. F., & Holst, J. J. (2013). Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes: comparison, efficacy and safety. Expert opinion on pharmacotherapy, 14(15), 2047-2058.
Esposito, K., Chiodini, P., Maiorino, M. I., Capuano, A., Cozzolino, D., Petrizzo, M., ... & Giugliano, D. (2015). A nomogram to estimate the HbA1c response to different DPP-4 inhibitors in type 2 diabetes: a systematic review and meta-analysis of 98 trials with 24 163 patients. BMJ open, 5(2), e005892.
Evans, P. M., & Bain, S. C. (2016). Omarigliptin for the treatment of type 2 diabetes mellitus. Expert Opinion on Pharmacotherapy, 17(14), 1947-1952.
Fang, Y., Zhang, S., Wu, W., Liu, Y., Yang, J., Li, Y., ... & Yang, Z. (2020). Design and synthesis of tetrahydropyridopyrimidine derivatives as dual GPR119 and DPP-4 modulators. Bioorganic Chemistry, 94, 103390.
Florentin, M., Kostapanos, M. S., & Papazafiropoulou, A. K. (2022). Role of dipeptidyl peptidase 4 inhibitors in the new era of antidiabetic treatment. World Journal of Diabetes, 13(2), 85.
Fuh, M. T., Tseng, C. C., Li, S. M., Tsai, S. E., Chuang, T. J., Lu, C. H., ... & Wong, F. F. (2021). Design, synthesis and biological evaluation of glycolamide, glycinamide, and β-amino carbonyl 1, 2, 4-triazole derivatives as DPP-4 inhibitors. Bioorganic Chemistry, 114, 105049.
Fukushima, H., Hiratate, A., Takahashi, M., Saito-Hori, M., Munetomo, E., Kitano, K., ... & Yamamoto, K. (2008). Synthesis and Structure–Activity Relationships of Potent 1-(2-Substituted-aminoacetyl)-4-fluoro-2-cyanopyrrolidine Dipeptidyl Peptidase IV Inhibitors. Chemical and Pharmaceutical Bulletin, 56(8), 1110-1117.
Gallwitz, B. (2019). Clinical use of DPP-4 inhibitors. Frontiers in endocrinology, 10.
Gilbert, M. P., & Pratley, R. E. (2020). GLP-1 analogs and DPP-4 inhibitors in type 2 diabetes therapy: review of head-to-head clinical trials. Frontiers in endocrinology, 11, 178..
Graefe-Mody, U., Retlich, S., & Friedrich, C. (2012). Clinical pharmacokinetics and pharmacodynamics of linagliptin. Clinical pharmacokinetics, 51, 411-427.
He, Y. L. (2012). Clinical pharmacokinetics and pharmacodynamics of vildagliptin. Clinical pharmacokinetics, 51, 147-162.
Huneif, M. A., Alshehri, D. B., Alshaibari, K. S., Dammaj, M. Z., Mahnashi, M. H., Majid, S. U., ... & Sadiq, A. (2022). Design, synthesis and bioevaluation of new vanillin hybrid as multitarget inhibitor of α-glucosidase, α-amylase, PTP-1B and DPP4 for the treatment of type-II diabetes. Biomedicine & Pharmacotherapy, 150, 113038.
Jha, V., & Bhadoriya, K. S. (2018). Synthesis, pharmacological evaluation and molecular docking studies of pyrimidinedione based DPP-4 inhibitors as antidiabetic agents. Journal of Molecular Structure, 1158, 96-105.
Ji, X., Su, M., Wang, J., Deng, G., Deng, S., Li, Z., ... & Liu, H. (2014). Design, synthesis and biological evaluation of hetero-aromatic moieties substituted pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors. European journal of medicinal chemistry, 75, 111-122.
Ji, X., Xia, C., Wang, J., Su, M., Zhang, L., Dong, T., ... & Liu, H. (2014). Design, synthesis and biological evaluation of 4-fluoropyrrolidine-2-carbonitrile and octahydrocyclopenta [b] pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors. European Journal of Medicinal Chemistry, 86, 242-256.
Jiang, T., Zhou, Y., Zhu, J., Chen, Z., Sun, P., Zhang, Q., ... & Shen, J. (2015). Design, synthesis, and pharmacological evaluation of highly potent and selective dipeptidyl peptidase-4 inhibitors. Archiv der Pharmazie, 348(6), 399-407.
Johnson, K. M. (2010). Dutogliptin, a dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus. Current Opinion in Investigational Drugs (London, England: 2000), 11(4), 455-463.
Karasik, A., Aschner, P., Katzeff, H., Davies, M. J., & Stein, P. P. (2008). Sitagliptin, a DPP-4 inhibitor for the treatment of patients with type 2 diabetes: a review of recent clinical trials. Current medical research and opinion, 24(2), 489-496.
Keating, G. M. (2010). Vildagliptin: a review of its use in type 2 diabetes mellitus. Drugs, 70, 2089-2112.
Keating, G. M. (2015). Alogliptin: a review of its use in patients with type 2 diabetes mellitus. Drugs, 75, 777-796.
Kumar, S., Mittal, A., & Mittal, A. (2021). A review upon medicinal perspective and designing rationale of DPP-4 inhibitors. Bioorganic & Medicinal Chemistry, 46, 116354.
Li, N., Wang, L. J., Jiang, B., Guo, S. J., Li, X. Q., Chen, X. C., ... & Shi, D. Y. (2018). Design, synthesis and biological evaluation of novel pyrimidinedione derivatives as DPP-4 inhibitors. Bioorganic & Medicinal Chemistry Letters, 28(12), 2131-2135.
Li, Q., Zhou, M., Han, L., Cao, Q., Wang, X., Zhao, L., ... & Zhang, H. (2015). Design, synthesis and biological evaluation of Imidazo [1, 2-a] pyridine derivatives as novel DPP-4 inhibitors. Chemical biology & drug design, 86(4), 849-856.
Lotfy, M., Singh, J., Kalász, H., Tekes, K., & Adeghate, E. (2011). Suppl 2: Medicinal chemistry and applications of incretins and dpp-4 inhibitors in the treatment of type 2 diabetes mellitus. The open medicinal chemistry journal, 5, 82.
Makrilakis, K. (2019). The role of DPP-4 inhibitors in the treatment algorithm of type 2 diabetes mellitus: when to select, what to expect. International journal of environmental research and public health, 16(15), 2720.
Mcintosh, C. H., Demuth, H. U., Pospisilik, J. A., & Pederson, R. (2005). Dipeptidyl peptidase IV inhibitors: how do they work as new antidiabetic agents?. Regulatory peptides, 128(2), 159-165.
Mehanna, A. S., & Kelada, M. (2020). Design, synthesis, and in vitro evaluation of novel dipeptidyl peptidase IV inhibitors. Biomed Res, 5, 1-9.
Narsimha, S., Battula, K. S., Ravinder, M., Reddy, Y. N., & Nagavelli, V. R. (2020). Design, synthesis and biological evaluation of novel 1, 2, 3-triazole-based xanthine derivatives as DPP-4 inhibitors. Journal of Chemical Sciences, 132, 1-9.
Patel, B. D., Bhadada, S. V., & Ghate, M. D. (2017). Design, synthesis and anti-diabetic activity of triazolotriazine derivatives as dipeptidyl peptidase-4 (DPP-4) inhibitors. Bioorganic chemistry, 72, 345-358.
Ran, Y., Pei, H., Shao, M., & Chen, L. (2016). Synthesis, Biological Evaluation, and Molecular Docking of (R)-2-((8-(3-aminopiperidin-1-yl)-3-methyl-7-(3-methylbut-2-en-1-yl)-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-1-yl) methyl) benzonitrile as Dipeptidyl Peptidase IV Inhibitors. Chemical Biology & Drug Design, 87(2), 290-295.
Rollo, M. E., Aguiar, E. J., Williams, R. L., Wynne, K., Kriss, M., Callister, R., & Collins, C. E. (2016). eHealth technologies to support nutrition and physical activity behaviors in diabetes self-management. Diabetes, metabolic syndrome and obesity: targets and therapy, 381-390.
Saini, K., Sharma, S., & Khan, Y. (2023). DPP-4 inhibitors for treating T2DM-hype or hope? an analysis based on the current literature. Frontiers in Molecular Biosciences, 10, 1130625.
Schwehm, C., Li, J., Song, H., Hu, X., Kellam, B., & Stocks, M. J. (2015). Synthesis of new DPP-4 inhibitors based on a novel tricyclic scaffold. ACS Medicinal Chemistry Letters, 6(3), 324-328.
Sharma, M., Gupta, M., Singh, D., Kumar, M., & Kaur, P. (2012). Synthesis, evaluation and molecular docking of thiazolopyrimidine derivatives as dipeptidyl peptidase iv inhibitors. Chemical biology & drug design, 80(6), 918-928.
Sortino, M. A., Sinagra, T., & Canonico, P. L. (2013). Linagliptin: a thorough characterization beyond its clinical efficacy. Frontiers in endocrinology, 4, 16.
Syam, Y. M., Anwar, M. M., Abd El-Karim, S. S., Elseginy, S. A., Essa, B. M., & Sakr, T. M. (2021). New quinoxaline compounds as DPP-4 inhibitors and hypoglycemics: design, synthesis, computational and bio-distribution studies. RSC advances, 11(58), 36989-37010.
Tahrani, A. A., Piya, M. K., & Barnett, A. H. (2009). Saxagliptin: a new DPP-4 inhibitor for the treatment of type 2 diabetes mellitus. Advances in therapy, 26, 249-262.
Tan, X. (2016). Omarigliptin for the treatment of type 2 diabetes. Endocrine, 54(1), 24-31.
Temel, H. E., Altintop, M. D., Sever, B., Özdemir, A., & Akalin Çiftçi, G. (2022). In vitro evaluation of 2-pyrazoline derivatives as DPP-4 inhibitors. Turkish Journal of Biochemistry, 48(1), 104-109.
Wang, J., Feng, Y., Ji, X., Deng, G., Leng, Y., & Liu, H. (2013). Synthesis and biological evaluation of pyrrolidine-2-carbonitrile and 4-fluoropyrrolidine-2-carbonitrile derivatives as dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes. Bioorganic & medicinal chemistry, 21(23), 7418-7429.
Wang, Y., Tang, X., & Yi, L. (2019). Design and discovery of novel 1, 3, 5-triazines as dipeptidyl peptidase-4 inhibitor against diabetes. Pharmacology, 103(5-6), 273-281.
Zhang, C., Ye, F., Wang, J., He, P., Lei, M., Huang, L., ... & Yan, P. (2020). Design, synthesis, and evaluation of a series of novel super long-acting DPP-4 inhibitors for the treatment of type 2 diabetes. Journal of Medicinal Chemistry, 63(13), 7108-7126.
Zhu, L., Li, Y., Qiu, L., Su, M., Wang, X., Xia, C., ... & Shen, J. (2013). Design and synthesis of 4-(2, 4, 5-trifluorophenyl) butane-1, 3-diamines as dipeptidyl peptidase IV inhibitors. ChemMedChem, 8(7), 1104-1116.
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