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24 条记录 (耗时 0.031 秒)

    FXR modulators
    14.
    发明授权
    FXR modulators 失效

    公开(公告)号：US06777446B2

    公开(公告)日：2004-08-17

    申请号：US09945293

    申请日：2001-08-31

    申请人： Jonathan Houze ,  Sharon McKendry ,  Joshua P. Gergely ,  Yi Xia ,  Bei Shan ,  Frank Kayser

    发明人： Jonathan Houze ,  Sharon McKendry ,  Joshua P. Gergely ,  Yi Xia ,  Bei Shan ,  Frank Kayser

    IPC分类号： A61K31166

    CPC分类号： C07D209/48 ,  C07C233/75 ,  C07C237/22 ,  C07C311/19 ,  C07C311/29 ,  C07C2601/14 ,  C07D241/44 ,  C07D279/02

    摘要： The present invention provides compounds, pharmaceutical compositions and methods that are useful in modulating the farnesoid X receptor (FXR). As FXR is involved in negatively controlling the expression level of cholesterol 7&agr;-hydroxylase (cyp7a), the rate-limiting enzyme involved in the oxidative metabolism of cholesterol into bile acids, the compounds described herein find utility in treating diseases associated with abnormally high or low cholesterol levels. In certain aspects, the FXR modulators (e.g., antagonists) described herein block the negative feed-back downregulation of cyp7a expression produced by certain cholic acids, the endogenous ligands for FXR. Moreover, as FXR forms heterodimers with the retinoid X receptor (RXR) in some cell types, modulation of the level of FXR activity in cells has a wide range of effects on a variety of biological processes which are mediated by RXR or other RXR-interacting proteins such as PPAR&ggr; and PPAR&agr;. Thus, compounds described herein are useful in treating other biological activities such as obesity, diabetes, lipid associated disorders, cancer, inflammatory disorders, disorders involving a disrupted or dysfunctional epidermal barrier, and various other metabolic disorders.

    Certain polycyclic compounds useful as tubulin-binding agents
    18.
    发明授权
    Certain polycyclic compounds useful as tubulin-binding agents 失效
    某些多环化合物可用作微管蛋白结合剂

    公开(公告)号：US06433187B1

    公开(公告)日：2002-08-13

    申请号：US09464217

    申请日：1999-12-15

    申请人： David Clark ,  Walter Frankmoelle ,  Jonathan Houze ,  Juan C. Jaen ,  Julio C. Medina

    发明人： David Clark ,  Walter Frankmoelle ,  Jonathan Houze ,  Juan C. Jaen ,  Julio C. Medina

    IPC分类号： C07D33708

    CPC分类号： C07D401/06 ,  A61K31/382 ,  C07C311/20 ,  C07C311/21 ,  C07C2603/30 ,  C07C2603/32 ,  C07D409/06 ,  C07D409/14 ,  C07D493/04

    摘要： Derivatives of known tubulin-binding compounds are provided in which a (poly)fluorobenzene, a fluoropyridine, or a fluoronitrobenzene moiety is incorporated or added to the structure. These derivatives can be used as antimitotic agents and can be considered covalent modifiers of tubulin. The strategy developed for each of the compounds is to i) append a fluorinated electrophile (e.g., pentafluorophenylsulfonamido, 2-fluoropyridyl, or 3,5-dinitro-4-fluorophenyl) to an existing functional group in a natural product, ii) replace an aromatic ring in a natural product with a fluorinated electrophile, or iii) attach a fluorinated electrophile to an open valence in a portion of the molecule that will not interfere with recognition and binding to the tubulin site. Derivatives are provided based on colchicine, steganacin, podophyllotoxin, nocodazole, combretastatin, curacin A, vinblastine, vincristine, dolastatin, 2-methoxyestradiol, dihydroxy-pentamethoxyflavanone and others.

    摘要翻译： 提供了已知的微管蛋白结合化合物的衍生物，其中（聚）氟苯，氟代吡啶或氟硝基苯部分被结合或添加到该结构中。 这些衍生物可用作抗有丝分裂剂并且可以被认为是微管蛋白的共价修饰剂。 为每种化合物制定的策略是i）将天然产物中的现有官能团上的氟化亲电体（例如五氟苯基磺酰胺基，2-氟吡啶基或3,5-二硝基-4-氟苯基） 具有氟化亲电体的天然产物中的芳香环，或iii）在分子的一部分中将氟化亲电体连接至开放价态，其不会干扰识别和结合微管蛋白位点。 衍生物基于秋水仙碱，steganacin，鬼臼毒素，诺考达唑，考布他汀，curacin A，长春花碱，长春新碱，多卡他汀，2-甲氧基雌二醇，二羟基 - 五甲氧基黄酮等。