The Design And Synthesis Of Vesnarinone Analogous As Positive Inotropic Agents

Based on the "bioisosteres and combination principles", which were widely used in design strategy of new drugs. Based on the structure of vesnarinone, seven series,117new compounds have been synthesized and evaluated for positive inotropic activity by measuring left atrium stroke volume on isolated rabbit-heart preparations. Some of these derivatives exhibited favorable activity compared with the standard drug, milrinone. The structures of the desired compounds were characterized by1H-NMR, mass spectra. Part of the compounds was also characterized by13C-NMR and IR.The research of this dissertation could be divided into three chapters as follows:(1) Four series of acetamides derivatives were designed, synthesized and evaluated for their positive inotropic activity in vitro. Results revealed that several series of the compounds exhibited good positive inotropic potency, most of the derivatives exhibited better in vitro. positive inotropic activity than the existing drug, milrinone, among which8a proved to be the most potent with20.29±0.18%increased stroke volume (milrinone:2.46±0.07%) at a concentration of3×10-5, was8-fold more potent in its activity than milrinone.(2) A series of quinoxalin derivatives were designed, synthesized and evaluated for their positive inotropic activity in vitro. Results revealed that only a few of the compounds exhibited good positive inotropic activity than milrinone, among which14k proved to be the most potent with5.34±0.05%increased stroke volume (milrinone:2.46±0.07%) at a concentration of3×10-5, was2-fold more potent in its activity than milrinone.(3) Two series of phthalazine derivatives were designed, synthesized and evaluated for their positive inotropic activity in vitro. Results revealed that most of the compounds reached the expected activity, among which25m proved to be the most potent with12.02±0.20%increased stroke volume (milrinone:2.46±0.07%) at a concentration of3×10-5, was5-fold more potent in its activity than milrinone. In this paper, based on the structure of vesnarinone, all the compounds were synthesized were evaluated for their in vitro positive inotropic activity. Activity screening results showed that most of the compounds reached the expected activity. And some of the target compounds exhibited considerable potency which were more potent positive inotropic activity than the existing drug, milrinone. These results are consistent to our original assumption and the bioassay results.