Design and synthesis of 4,5-diphenyl-4-isoxazolines: Novel inhibitors of cyclooxygenase-2 with analgesic and antiinflammatory activity
Design and synthesis of 4,5-diphenyl-4-isoxazolines: Novel inhibitors of cyclooxygenase-2 with analgesic and antiinflammatory activity
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DOI：
10.1021/jm0101287
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发表时间：
2001-08-30
影响因子：
7.3
通讯作者：
Knaus, EE
中科院分区：
文献类型：
--
作者：
Habeeb, AG;Rao, PNP;Knaus, EE
合成了一系列苯环帕拉上含有不同取代基（H，F，MeS，MeSO 2）的4，5-二苯基-4-异恶唑啉（13 a-k），并对其镇痛和选择性抑制环氧合酶-2（考克斯-2）的活性进行了评价。虽然不具有C-3 Me取代基的4，5-苯基-4-异恶唑啉（13 a-d，f）显示出有效的镇痛和AI活性，但所评价的那些化合物（13 a，13 b，13 h和13 k）不是考克斯-2的选择性抑制剂。相比之下，2，3-二甲基-5-（4-甲基磺酰基苯基）-4-苯基-4-异恶唑啉（13 j）表现出出色的镇痛和AI活性，并且是一种有效且选择性的考克斯-2抑制剂（考克斯-1，IC 50 = 258 μ M;考克斯-2，IC 50 = 0.004 μ M）。在4-苯基环的帕拉具有F取代基的相关化合物13 k也是选择性的（SI = 3162），但比13 j效力低（IC 50 = 0.0316 μ M）的考克斯-2抑制剂。13 j的分子模拟（对接研究）表明，MeSO 2取代基的S原子位于考克斯-2二级口袋（瓦尔（523））入口内侧约6.46埃处，并且C-3 Me（13 j，13 k）中心异恶唑啉环取代基对于这类化合物选择性抑制考克斯-2是至关重要的。
4,5-Diphenyl-4-isoxazolines (13a-k) possessing a variety of substituents (H, F, MeS, MeSO2) at the para position of one of the phenyl rings were synthesized for evaluation as analgesic and selective cyclooxygenase-2 (COX-2) inhibitory antiinflammatory (AI) agents. Although the 4,5-phenyl-4-isoxazolines (13a-d,f), which do not have a C-3 Me substituent, exhibited potent analgesic and AI activities, those compounds evaluated (13a, 13b, 13h, and 13k) were not selective inhibitors of COX-2. In contrast, 2,3-dimethyl-5-(4-methylsulfonylphenyl)-4-phenyl-4-isoxazoline (13j) exhibited excellent analgesic and AI activities, and it was a potent and selective COX-2 inhibitor (COX-1, IC50 = 258 muM; COX-2, IC50 = 0.004 muM). A related compound 13k having a F substituent at the para position of the 4-phenyl ring was also a selective (SI = 3162) but less potent (IC50 = 0.0316 muM) inhibitor of COX-2 than 13j. A molecular modeling (docking study) for 13j showed that the S atom of the MeSO2 substituent is positioned about 6.46 Angstrom inside the entrance to the COX-2 secondary pocket (Val(523)) and that a C-3 Me (13j, 13k) central isoxazoline ring substituent is crucial to selective inhibition of COX-2 for this class of compounds.