Design, Synthesis And Biological Evaluation Of Imidazol(Idine)Ones And Cyanopyrrolidines As Dipeptidyl Peptidase â…£ Inhibitors

Diabetes, which has a high incidence rate in China, is also a major threat to human health worldwide. Application of existing antidiabetic agents, unfortunately, could hardly cure or even prevent progression of the disease, and were often accompanied by adverse effects such as weigh gain, hypoglycemia and gastrointestinal disturbances. Therefore, the development of novel antidiabetic drugs is of urgent significance. Among recent strategies in treating diabetes, the study on small molecule DPP-IV inhibitors has raised as a research hotspot.Based on literature searching and study,88target compounds within five structural scaffolds were designed and synthesized in this thesis by using strategies including scaffold hopping, bioisosterism, hybrid pharmacophore and computer-aided drug design. Some synthesized target compounds showed potent inhibitory activity and favorable selectivity for DPP-IV.Design, synthesis, and evaluation of DPP-â…£ inhibitory activity of imidazolone and imdazolinedione derivatives is the first part of the thesis.12target molecules were synthesized starting from the lead compound, alogliptin, whose main pharmacophores were retaied and pyrimidione moiety was replaced by an imidazolone moiety. Modifications were also made to the substituents at the N-1, N-3,4, and5position of the scaffold. In addition,6imidazolinedione derivatives were designed and synthesized utilizing a rational drug strategy based on the obtained result. Evaluation of DPP-IV inhibitory activity and preliminary structure-activity relationship (SAR) revealed that firstly, substituents at N-1, N-3,4, and5positions had a significant impact on activity, and secondly, imidazolinedione derivatives displayed rather weak inhibitory activity against DPP-â…£.The second part of the thesis described the design, synthesis, and evaluation of DPP-IV inhibitory activity of cyanopyrrolidine-thiazolidinedione derivatives.17novel cyanopyrrolidine-thiazolidinedione derivatives were designed and synthesized by using NVP-728, a DPP-IV inhibitor that entered phase II clinical trials, as the lead compound. The N-glycinyl-2-cyanopyrrolidine moiety of NVP-728was retained with modifications made on substituents at the a-N position. Also the hybrid strategy between the thiazolidinedione scaffold of PPARy agonists and NVP-728was utilized. Structural diversity was achieved by the introduction of different substituents at the5position of the thiazolidinedione scaffold. Evaluation of DPP-â…£ inhibitory activity showed that only limited target compounds showed moderate DPP-â…£ inhibitory activity.The third part of the thesis is on the design, synthesis, and biological evaluation of cyanopyrrolidine-(S)-phenylalanine and cyanopyrrolidine-alanine derivatives. Firstly,16cyanopyrrolidine-(S)-phenylalanine and8cyanopyrrolidine-alanine derivatives were designed and synthesized assisted by using a molecule docking strategy.29cyanopyrrolidine-(S)-phenylalanine derivatives were further designed and synthesized based on obtained structure-activity relationships. The result of biological evaluation revealed that most compounds showed potent DPP-IV inhibitory activity with24compounds showed more potent inhibitory activity than that of the positive control sitagliptin. Besides, this series of synthesized compounds showed better selectivity over DPP-IV related enzymes including DPP-7, DPP-8and DPP-9, while the selectivity over FAP was poor. Preliminary structure-activity relationships are as follows: cyanopyrrolidine-(S)-phenylalanine derivatives, especially1,2,3-triazole substituted cyanopyrrolidine-(S)-phenylalanine derivatives, showed potent activity and favorable selectivity against DPP-â…£. It also revealed that the substituents at N-1position of the1,2,3-triazole ring had a significant impact on activity and selectivity.Two representative compounds3-105and3-117with high inhibitory activity and selectivity were then evaluated in an oral glucose tolerance test, the result of which showed that these two compounds significantly reduced blood glucose in normal rats. Also, compounds3-105and3-117showed no obvious cytotoxicity in cellular assays.