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    Neuroprotective poly-guanidino compounds which block presynaptic N and P/Q calcium channels
    1.
    发明授权
    Neuroprotective poly-guanidino compounds which block presynaptic N and P/Q calcium channels 失效
    阻断突触前N和P / Q钙通道的神经保护性聚胍苷

    公开(公告)号：US6063819A

    公开(公告)日：2000-05-16

    申请号：US26415

    申请日：1998-02-18

    申请人： Paul J. Marangos ,  Brian W. Sullivan ,  Torsten Wiemann ,  Anne M. Danks ,  Marina Sragovicz ,  Lewis R. Makings

    发明人： Paul J. Marangos ,  Brian W. Sullivan ,  Torsten Wiemann ,  Anne M. Danks ,  Marina Sragovicz ,  Lewis R. Makings

    IPC分类号： A61K31/00 ,  A61K31/155 ,  A61K31/16 ,  A61K31/165 ,  A61K38/05 ,  A61K31/55 ,  C07C233/05

    CPC分类号： A61K38/05 ,  A61K31/00 ,  A61K31/155 ,  A61K31/16 ,  A61K31/165

    摘要： Neuroprotective drugs are disclosed with at least 3 branches extending outwardly from a center atom or group, each branch having a guanidino group at its terminus. All branches preferably should be identical, and distributed around the center atom or group in a radial manner. Three branches can be bonded to a nitrogen atom, or four branches can be coupled to a carbon atom; other center groups include stable aromatic, cycloalkyl, heterocyclic, or bicyclic structures. Starting reagents are disclosed with a center atom or group, and with reactive groups (such as primary amines or hydroxyl groups) at the ends of short "spacer chains" bonded to the center atom or group. Reagents derived from arginine (an amino acid having a terminal guanidino group) can be bonded to these center components, using protective groups on the arginyl reagents to ensure desired final products with accessible guanidino groups at the ends of spacer chains. Alternately, guanylating agents can be used to directly convert primary amine groups at the ends of spacer chains, on starting reagents, into guanidino groups. These drugs can be injected intravenously into patients suffering from ischemic or hypoxic crises (stroke, cardiac arrest, loss of blood, suffocation, etc.), and can penetrate the blood-brain barrier and suppress the entry of calcium into CNS neurons via N-type and P/Q-type calcium channels, thereby reducing excitotoxic damage in the CNS. These drugs are also useful for suppressing other types of unwanted excessive neuronal activation, such as neuropathic pain.

    摘要翻译： 公开了具有从中心原子或基团向外延伸的至少3个分支的神经保护药物，每个分支在其末端具有胍基。 所有分枝优选应该相同，并以径向方式分布在中心原子或基团周围。 三个分支可以键合到氮原子上，或者四个分支可以与碳原子结合; 其它中心基团包括稳定的芳族，环烷基，杂环或双环结构。 起始试剂用中心原子或基团和与中心原子或基团键合的短“间隔链”末端的反应性基团（例如伯胺或羟基）公开。 衍生自精氨酸（具有末端胍基的氨基酸）的试剂可以使用精氨酰试剂上的保护基团键合到这些中心组分，以确保在间隔链末端具有可及的胍基的所需最终产物。 或者，脒基化剂可用于直接将起始试剂的间隔链末端的伯胺基转化成胍基。 这些药物可以静脉注射给患有缺血性或缺氧危象（中风，心跳停止，血液流失，窒息等）的患者，并可以穿透血脑屏障并抑制钙通过N- 类型和P / Q型钙通道，从而减少CNS中的兴奋性毒性损伤。 这些药物也可用于抑制其他类型的不想要的过量神经元激活，例如神经性疼痛。

    Optical molecular sensors for cytochrome P450 activity
    4.
    发明申请
    Optical molecular sensors for cytochrome P450 activity 审中-公开

    公开(公告)号：US20080125586A1

    公开(公告)日：2008-05-29

    申请号：US11953770

    申请日：2007-12-10

    申请人： Lewis R. Makings ,  Gregory Zlokarnik

    发明人： Lewis R. Makings ,  Gregory Zlokarnik

    IPC分类号： C07D265/38 ,  C07D327/04 ,  C07D311/74 ,  C07D311/82

    CPC分类号： C07D493/10 ,  C07D219/06 ,  C07D265/38 ,  C07D311/16 ,  C07D311/82 ,  C12Q1/26 ,  G01N2333/90245 ,  G01N2500/02 ,  Y10S435/968

    摘要： The invention provides a compound, useful as an optical probe or sensor of the activity of at least one cytochrome P450 enzyme, and methods of using the compound to screen candidate drugs, and candidate drugs identified by these methods. The optical probe of the invention is a compound having the generic structure Y-L-Q, wherein Y is selected from the group consisting of Q as herein defined, saturated C1-C20 alkyl, unsaturated C1-C20 alkenyl, unsaturated C1-C20 alkynyl, substituted saturated C1-C20 alkyl, substituted unsaturated C1-C20 alkenyl, substituted unsaturated C1-C20 alkynyl, C1-C20 cycloalkyl, C1-C20 cycloalkenyl, substituted saturated C1-C20 cycloalkyl, substituted unsaturated C1-C20 cycloalkenyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; L is selected from the group of (—OCR2H)p—, wherein for each p, all R2 are separately selected from the group consisting of a hydrogen atom, saturated C1-C20 alkyl, unsaturated C1-C20 alkenyl, unsaturated C1-C20 alkynyl, substituted saturated C1-C20 alkyl, substituted unsaturated C1-C20 alkenyl, substituted unsaturated C1-C20 alkynyl, C1-C20 cycloalkyl, C1-C20 cycloalkenyl, substituted saturated C1-C20 cycloalkyl, substituted unsaturated C1-C20 cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and p is a positive integer no greater than twelve; and Q is a chemical moiety that gives rise to optical properties in its hydroxy or hydroxylate, phenol or phenoxide form that are different from the optical properties that arise from its ether form. Most preferably, p is one, R2 is hydrogen, and Q is the ether form of a phenoxide fluorophore.

    Optical molecular sensors for cytochrome P450 activity
    5.
    发明授权
    Optical molecular sensors for cytochrome P450 activity 有权
    用于细胞色素P450活性的光学分子传感器

    公开(公告)号：US06420130B1

    公开(公告)日：2002-07-16

    申请号：US09301525

    申请日：1999-04-28

    申请人： Lewis R. Makings ,  Gregor Zlokarnik

    发明人： Lewis R. Makings ,  Gregor Zlokarnik

    IPC分类号： C07D27918

    CPC分类号： C07D493/10 ,  C07D219/06 ,  C07D265/38 ,  C07D311/16 ,  C07D311/82 ,  C12Q1/26 ,  G01N2333/90245 ,  G01N2500/02 ,  Y10S435/968

    摘要： The invention provides a compound, useful as an optical probe or sensor of the activity of at least one cytochrome P450 enzyme, and methods of using the compound to screen candidate drugs, and candidate drugs identified by these methods. The optical probe of the invention is a compound having the generic structure Y—L—Q, wherein Y is selected from the group consisting of Q as herein defined, saturated C1-C20 alkyl, unsaturated C1-C20 alkenyl, unsaturated C1-C20 alkynyl, substituted saturated C1-C20 alkyl, substituted unsaturated C1-C20 alkenyl, substituted unsaturated C1-C20 alkyl, C1-C20 cycloalkyl, C1-C20 cycloalkenyl, substituted saturated C1-C20 cycloalkyl, substituted unsaturated C1-C20 cycloalkenyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; L is selected from the group of (—OCR2H)p—, wherein for each p, all R2 are separately selected from the group consisting of a hydrogen atom, saturated C1-C20 alkyl, unsaturated C1-C20 alkenyl, unsaturated C1-C20 alkynyl, substituted saturated C1-C20 alkyl, substituted unsaturated C1-C20 alkenyl, substituted unsaturated C1-C20 alkyl, C1-C20 cycloalkyl, C1-C20 cycloalkenyl, substituted saturated C1-C20 cycloalkyl, substituted unsaturated C1-C20 cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and p is a positive integer no greater than twelve; and Q is a chemical moiety that gives rise to optical properties in its hydroxy or hyrdoxylate, phenol or phenoxide form that are different from the optical properties that arise from its ether form. Most preferably, p is one, R2 is hydrogen, and Q is the ether form of a phenoxide fluorophore.

    摘要翻译： 本发明提供了可用作至少一种细胞色素P450酶的活性的光学探针或传感器的化合物，以及使用该化合物筛选候选药物的方法以及通过这些方法鉴定的候选药物。 本发明的光学探针是具有一般结构YLQ的化合物，其中Y选自本文定义的Q，饱和C 1 -C 20烷基，不饱和C 1 -C 20烯基，不饱和C 1 -C 20炔基，取代的饱和C 1 -C 20烷基，取代的不饱和C 1 -C 20烯基，取代的不饱和C 1 -C 20烷基，C 1 -C 20环烷基，C 1 -C 20环烯基，取代的饱和C 1 -C 20环烷基，取代的不饱和C 1 -C 20环烯基，芳基，取代的芳基， 杂芳基; L选自（-OCR 2 H）p - ，其中对于每个p，所有的R 2分别选自氢原子，饱和C 1 -C 20烷基，不饱和C 1 -C 20烯基，不饱和C 1 -C 20炔基 取代的饱和C 1 -C 20烷基，取代的不饱和C 1 -C 20烯基，取代的不饱和C 1 -C 20烷基，C 1 -C 20环烷基，C 1 -C 20环烯基，取代的饱和C 1 -C 20环烷基，取代的不饱和C 1 -C 20环烯基，芳基， 杂芳基，取代的杂芳基，p是不大于12的正整数; 并且Q是一种化学部分，其产生与其醚形式产生的光学性质不同的其羟基或羟乙酸酯，苯酚或酚盐形式的光学性质。 最优选地，p是1，R2是氢，Q是醚形式的苯氧基荧光团。