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    Non-calcemic, antiproliferative, transcriptionally active 24-fluorinated hybrid analogs of 1.alpha.,-25-dihydroxy vitamin D.sub.3
    2.
    发明授权
    Non-calcemic, antiproliferative, transcriptionally active 24-fluorinated hybrid analogs of 1.alpha.,-25-dihydroxy vitamin D.sub.3 有权
    1α，-25-二羟维生素D3的非钙血症，抗增殖，转录活性的24-氟化杂合类似物

    公开(公告)号：US6043386A

    公开(公告)日：2000-03-28

    申请号：US323106

    申请日：1999-06-01

    申请人： Gary H. Posner ,  Jae Kyoo Lee ,  Qiang Wang

    发明人： Gary H. Posner ,  Jae Kyoo Lee ,  Qiang Wang

    IPC分类号： A61K31/59 ,  C07C401/00

    CPC分类号： A61K31/59

    摘要： Fluorinated analogs of 1.alpha.,25-dihydroxyvitamin D.sub.3. These analogs are synthesized in a convergent manner by joining A-ring and C,D-ring fragments. Each hybrid analog, having a calcemia-lowering 1-hydroxymethyl group and a potentiating 16-ene-24,24-difluorinated C,D-ring and side chain, is designed to be lipophilic and inert toward 24-hydroxylase enzyme catabolism. Each hybrid analog with 1.beta.,3.alpha.-substituent stereochemistry shows a pharmacologically desirable combination of high antiproliferative and high transcriptional activities in vitro and also low calcemic activity in vivo.

    摘要翻译： 1α，25-二羟基维生素D3的氟化类似物。 这些类似物通过连接A环和C，D环片段以收敛方式合成。 具有降钙素1-羟甲基和增强的16-烯-2,24,24-二氟化C，D-环和侧链的每种杂合类似物被设计为亲脂性并且对24-羟化酶分解代谢是惰性的。 具有1β，3α-取代立体化学的每种杂合类似物在体外显示高度抗增殖和高转录活性的药理学上期望的组合，并且还体内低钙活性。

    VITAMIN D3 ANALOG LOADED POLYMER FORMULATIONS FOR CANCER AND NEURODEGENERATIVE DISORDERS
    3.
    发明申请
    VITAMIN D3 ANALOG LOADED POLYMER FORMULATIONS FOR CANCER AND NEURODEGENERATIVE DISORDERS 审中-公开
    VITAMIN D3模拟装载聚合物制剂用于癌症和神经损伤性疾病

    公开(公告)号：US20080260834A1

    公开(公告)日：2008-10-23

    申请号：US12165036

    申请日：2008-06-30

    申请人： Martin Burke ,  Maria-Christina White ,  Mark C. Watts ,  Jae Kyoo Lee ,  Betty M. Tyler ,  Gary H. Posner ,  Henry Brem

    发明人： Martin Burke ,  Maria-Christina White ,  Mark C. Watts ,  Jae Kyoo Lee ,  Betty M. Tyler ,  Gary H. Posner ,  Henry Brem

    IPC分类号： A61K31/59 ,  A61K9/10 ,  A61P35/00 ,  A61P25/28

    CPC分类号： A61K9/0024 ,  A61K9/0085 ,  A61K9/1641

    摘要： Localized delivery of 1,25 D3 directly to a target area using biodegradable polymeric matrices maximizes the efficacy of this drug while minimizing systemic exposure and toxicity. Anticalcemic analogs of 1,25 D3 have also been incorporated into controlled release polymer formulations to achieve efficacious intracranial concentrations of 1,25 D3 analogs for the treatment of intracranial tumors as well as neurodegenerative disorders such as Alzheimer's disease as well as to maximize the efficacy of these analogs in the treatment of systemic malignancies. The therapeutic efficacy of these formulations was demonstrated through a variety of studies in vitro and in vivo. Hybrid analogs of 1,25 D3 were incorporated into biodegradable polymer wafers composed of a polyanhydride copolymer of 1,3-bis(p-carboxyphenoxy)propane (CPP) and sebacic acid (SA) in a 20:80 molar ratio. In addition to providing improved treatments for malignancies and neurodegenerative disorders, the spatial localization and high reproducibility of this controlled delivery methodology presents a unique opportunity to study in vivo the poorly understood mechanisms of 1,25 D3's antiangiogenic, antiproliferative, and transcriptional regulating activities.

    摘要翻译： 使用可生物降解的聚合物基质直接向目标区域局部递送1,25 D 3 N使该药物的功效最大化，同时使全身暴露和毒性最小化。 1,25 D 3 N的类似物也被并入控释聚合物制剂中，以实现颅内肿瘤治疗的有效颅内浓度1,25D 3 N 3类似物 以及神经变性疾病如阿尔茨海默病，以及使这些类似物在治疗全身性恶性肿瘤中的功效最大化。 通过体外和体内的各种研究证实了这些制剂的治疗功效。 将1,25 D 3 N的混合类似物掺入到由20重量份的1,3-双（对羧基苯氧基）丙烷（CPP）和癸二酸（SA）的聚酐共聚物组成的可生物降解的聚合物晶片中 ：80摩尔比。 除了为恶性肿瘤和神经变性疾病提供改进的治疗之外，这种受控递送方法的空间定位和高重现性提供了一个独特的机会，可以在体内研究一个不太了解的1,25 D 3 抗血管生成，抗增殖和转录调节活性。