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    PYRAZOLE INHIBITORS OF COX-2 AND sEH
    5.
    发明申请
    PYRAZOLE INHIBITORS OF COX-2 AND sEH 审中-公开
    COX-2和SEH的吡唑抑制剂

    公开(公告)号：WO2012082647A2

    公开(公告)日：2012-06-21

    申请号：PCT/US2011/064474

    申请日：2011-12-12

    申请人： THE REGENTS OF THE UNIVERSITY OF CALIFORNIA ,  HAMMOCK, Bruce D. ,  HWANG, Sung Hee ,  WAGNER, Karen M. ,  MORISSEAU, Christophe ,  WECKSLER, Aaron T. ,  ZHANG, Guodong

    发明人： HAMMOCK, Bruce D. ,  HWANG, Sung Hee ,  WAGNER, Karen M. ,  MORISSEAU, Christophe ,  WECKSLER, Aaron T. ,  ZHANG, Guodong

    CPC分类号： C07D231/12 ,  C07D231/14 ,  C07D231/40

    摘要： The present invention provides compounds and compositions, e.g., a series of compounds wherein a 1,5-biarylpyrazole group is conjugated to a urea group by a non-cleavable covalent chain, that are useful as dual COX-2/sEH inhibitors. The compounds disclosed herein have activity associated with the arachidonate cascade. The activity of these compounds was demonstrated using a lipopolysaccharide (LPS) induced model of pain in the rat. The compounds of the present invention demonstrated superior anti-allodynic activity as compared to the same dose of celecoxib, i.e. , a COX-2 inhibitor, also as compared to the same dose of t-AUCB, i.e. , a sEH inhibitor, and also as compared to the co-administered same dose of both celecoxib and t-AUCB. The dual inhibitors of the present invention demonstrate enhanced in vivo anti-allodynic activity in a nociceptive behavioral assay. In addition, the compounds of the present invention also demonstrated to have potent anti-angiogenic effects toward endothelial cells (HUVEC) and inhibit angiogenesis in vitro , ex vivo and in vivo . The dual inhibitors of the present invention also demonstrate anti-angiogenic effect to slow breast tumor growth in vivo .

    摘要翻译： 本发明提供化合物和组合物，例如一系列化合物，其中1,5-双芳基吡唑基团可通过不可裂解的共价链与脲基团缀合，其可用作双重COX-2 / sEH抑制剂。 本文公开的化合物具有与花生四烯酸级联相关的活性。 使用脂多糖（LPS）诱导的大鼠疼痛模型证明了这些化合物的活性。 与相同剂量的塞来昔布（即，COX-2抑制剂）相比，本发明的化合物与同样剂量的t-AUCB（即sEH抑制剂）相比，表现出优异的抗异常性疼痛活性，并且还作为 与联合给药相同剂量的塞来昔布和t-AUCB相比。 本发明的双重抑制剂在伤害性行为测定中表现出增强的体内抗异常性疼痛活性。 此外，本发明的化合物还证明对体内，体内和体内对内皮细胞（HUVEC）具有有效的抗血管生成作用并抑制血管生成。 本发明的双重抑制剂还表现出对血管内肿瘤生长缓慢的抗血管生成作用。