1,5-二芳基吡唑类环加氧酶-2选择性抑制剂的定量构效关系

Quantitative structure-activity relationship of the 1,5-diarylpyrazole class of cyclooxygenase-2 selective inhibitors

目的 :探讨 1,5 二芳基吡唑类环加氧酶 2选择性抑制剂分子结构与活性定量关系 ,建立反映该类化合物构效关系的数学模型 ,为进一步药物设计提供理论依据 .方法 :按类型衍化出的先导化合物 ,采用多元回归分析方法 ,将 2 2个 5 取代吡唑化合物的环加氧酶 1抑制活性 ,环加氧酶 2抑制活性和抑制选择性与化合物疏水性参数logP ,取代基电性参数幃,立体参数MR进行相关及定量构效分析 .结果 :得到 3个反映该类抑制剂活性及选择性的定量构效关系 (QSAR)方程 :PIC50 ,COX -1=8.789838(1.76 81) - 0 .4 0 75 92 5 (0 .1839)logP ;PIC50 ,COX 2 =6 .4 374 34(0 .2 32 2 ) +0 .884 4 0 70 (0 .3487)logP 1.6 93330 (0 .5 0 0 3)Σ幃 ;Ps =- 6 1.18379(2 6 .10 91) +13.2 6 386(5 .5 6 937)logP - 0 .6 875 0 92 (0 .2 96 4 7) (logP) 2 .结论 :环加氧酶抑制选择性与疏水性呈抛物线关系 ;5位苯环 3,4位引入推电子基团或疏水性取代基 ,有利于提高该类化合物环加氧酶 2抑制活性 .所得QSAR方程可较好地预测该类化合物选择性抑制环加氧酶

AIM: To establish the QSAR models of the 1,5 diarylpyrazole class of COX 2 inhibitors and give the theoretical basis to guide the design of the new inhibitors. METHODS: Multiple correlation between activity and the physiochemical parameters of 22 derivatives was analyzed through the multiple regression analysis. RESULTS: According to the multiple regression analysis, three QSAR equations were acquired as follows: P IC50,COX 1 = 8.789838 (1.7681) -0.4075925(0.1839) logP;P IC50,COX 2 = 6.437434 (0.2322) +0.8844070(0.3487)logP-1.693330(0.5003)Σó; Ps= -61.18379(26.1091)+13.26386(5.56937)logP- 0.6875092 (0.29647)(logP) 2. CONCLUSION: In the series of 1, 5 diarylpyrazole, QSAR models reveal that the relationship between COX 2 selectivity and hydrophobic constant shows a parabolic change and that introduction of electron repelling and hydrophobic groups onto the 5 position of pheyl ring can raise the COX 2 inhibition activity.