| 摘要: | 在持續尋找新型抗血小板的藥物中，發現3-(5-methyl-2-furyl)- 1,5-diphenylpyrazole (3)具有好的抗血小板活性，機轉為抑制cyclic nucleotide phosphodiesterase 5 (PDE5) (IC50 = 4.21μM)。基於此結果，著者以化合物3為先導化合物，設計合成一系列1-substituted phenyl- 3-(5-methyl-2-furyl)-5-phenylpyrazoles (3, 5~12, 14~17) 與1-substituted phenyl-5-(5-methyl-2-furyl)-3-phenylpyrazoles (22, 23, 25~30, 34, 35, 37)及其相關類緣物(42, 43, 45, 46, 49, 50, 52, 55, 56, 57, 58, 59, 60, 61, 62)。
在實驗過程中，除預期之產物外，還有其他不預期產物之生成，藉由一維、二維核磁共振圖譜順利將結構完成解析，並且探討其可能生成之機轉。
將所合成之化合物提供抗血小板活性測試，部分結果顯示1-substituted phenyl-3-(5-methyl-2-furyl)-5-phenylpyrazoles (5~12, 14~17)對collagen (10 μg /ml)與ADP (20 μΜ)所誘導的血小板凝集抑制作用和化合物3相當。其中化合物5 (R = 4-Cl)，6 (R = 3-Cl)，8 (R = 4-F)，9 (R = 3-F)，10 (R = 2-F)對於AA (200 μM)所誘導的血小板凝集抑制作用則優於化合物3。至於U46619所誘導的血小板凝集抑制作用則仍以化合物3為最佳。
化合物3之位置異構物1-substituted phenyl-5-(5-methyl-2-furyl)- 3-phenylpyrazoles (22, 23, 25~30, 34, 35, 37)其抗血小板之活性則明顯低於1-substituted phenyl-3-(5-methyl-2-furyl)-5-phenylpyrazoles (3, 5~12, 14~17)。
As a part of our continuing search for novel aniplatelet agent, we had found 3-(5-methyl-2-furyl)-1,5-diphenylpyrazole (3) potent cyclic nucleotide phosphodiesterase 5 (PDE5) inhibition (IC50 = 4.21μM). Encourage by this result, the compound 3 was selcted as lead compound, a series of 1-substituted phenyl-3-(5-methyl-2-furyl)-5-phenylpyrazoles (3, 5~12, 14~17), 1-substituted phenyl-5-(5-methyl-2-furyl)-3-phenyl- pyrazoles (22, 23, 25~30, 34, 35, 37) and related analogs (42, 43, 45, 46, 49, 50, 52, 55, 56, 57, 58, 59, 60, 61, 62) were designed and synthesized in this work.
In addition to the product we expect, some unexpect compounds were also obtained. The structure elucidation of these compounds were performed by exploiting the 1D and 2D NMR spectra, and the possible mechanism of their formation were explored.
All the synthesized compounds test for their antiplatelet activity. The partial results showed that the inhibitory effect of 1-substituted phenyl- 3-(5-methyl-2-furyl)-5-phenylpyrazoles (5~12, 14~17) on platelet aggregation induced by collagen (10 μg /ml) and ADP (20 μΜ) are similar the compound 3. However, the inhibitory effect of 5 (R = 4-Cl), 6 (R = 3-Cl), 8 (R = 4-F), 9 (R = 3-F), 10 (R = 2-F) on platelet aggregation induced by AA (200 μM) are better than compound 3.
In addition to, the antiplatelet activity of the position isomers of compound 3, 1-substituted phenyl-5-(5-methyl-2-furyl)-3-phenyl- pyrazoles (22, 23, 25~30, 34, 35, 37) are inferior to 1-substituted phenyl-3-(5-methyl-2-furyl)-5-phenylpyrazoles (3, 5~12, 14~17). |
