Medicinal Chemistry and Molecular Modelling Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India.
Division of Bioinformatics, Indian Council of Medical Research, New Delhi 110029, India.
Molecules. 2023 Aug 3;28(15):5860. doi: 10.3390/molecules28155860.
This article sheds light on the various scaffolds that can be used in the designing and development of novel synthetic compounds to create DPP-4 inhibitors for the treatment of type 2 diabetes mellitus (T2DM). This review highlights a variety of scaffolds with high DPP-4 inhibition activity, such as pyrazolopyrimidine, tetrahydro pyridopyrimidine, uracil-based benzoic acid and esters, triazole-based, fluorophenyl-based, glycinamide, glycolamide, β-carbonyl 1,2,4-triazole, and quinazoline motifs. The article further explains that the potential of the compounds can be increased by substituting atoms such as fluorine, chlorine, and bromine. Docking of existing drugs like sitagliptin, saxagliptin, and vildagliptin was done using Maestro 12.5, and the interaction with specific residues was studied to gain a better understanding of the active sites of DPP-4. The structural activities of the various scaffolds against DPP-4 were further illustrated by their inhibitory concentration (IC) values. Additionally, various synthesis schemes were developed to make several commercially available DPP4 inhibitors such as vildagliptin, sitagliptin and omarigliptin. In conclusion, the use of halogenated scaffolds for the development of DPP-4 inhibitors is likely to be an area of increasing interest in the future.
本文探讨了可用于设计和开发新型合成化合物的各种支架，以创建用于治疗 2 型糖尿病（T2DM）的 DPP-4 抑制剂。本综述强调了多种具有高 DPP-4 抑制活性的支架，如吡唑并嘧啶、四氢嘧啶嘧啶、基于尿嘧啶的苯甲酸和酯、基于三唑的、基于氟苯基的、甘氨酰胺、甘醇酰胺、β-羰基 1,2,4-三唑和喹唑啉基序。文章进一步解释说，通过取代氟、氯和溴等原子，可以提高化合物的潜力。使用 Maestro 12.5 对西他列汀、沙格列汀和维达列汀等现有药物进行对接，并研究与特定残基的相互作用，以更好地了解 DPP-4 的活性部位。通过它们的抑制浓度（IC）值进一步说明了各种支架对 DPP-4 的结构活性。此外，还开发了各种合成方案来制备几种市售的 DPP4 抑制剂，如维达列汀、西他列汀和奥马格列汀。总之，未来使用卤化支架来开发 DPP-4 抑制剂可能是一个日益受到关注的领域。
