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    CBI ANALOGUES OF THE DUOCARMYCINS AND CC-1065
    4.
    发明申请
    CBI ANALOGUES OF THE DUOCARMYCINS AND CC-1065 审中-公开
    。。。。。。。。。。。

    公开(公告)号：WO2004101767A2

    公开(公告)日：2004-11-25

    申请号：PCT/US2004/015221

    申请日：2004-05-13

    Applicant: THE SCRIPPS RESEARCH INSTITUTE ,  BOGER, Dale, L.

    Inventor： BOGER, Dale, L.

    IPC: C12N

    CPC classification number: C07D209/94 ,  C07D209/60 ,  C07D405/06

    Abstract: An extensive series of CBI analogues of the duocarmycins and CC-1065 exploring substituent effects within the first indole DNA binding subunit is detailed. In general, substitution at the indole C5 position led to cytotoxic potency enhancements that can be ≥ 1000-fold providing simplified analogues containing a single DNA binding subunit that are more potent (IC 50 = 2-3 pM) than CBI-TMI, duocarmycin SA, or CC-1065. The increases in cytotoxicity correlate well with accompanying increases in the rate and efficiency of DNA alkylation. This effect is more pronounced with the CBI versus DSA or CPI based analogues. Moreover, this effect is largely insensitive to the electronic character of the C5 substituent but is sensitive to the size, rigid length, and shape (sp, sp 2 , sp 3 hybridization) of this substituent consistent with expectation that the impact is due simply to its presence.

    Abstract translation: 详细介绍了广泛的一系列CBO类似物的二十多环素和CC-1065探索第一个吲哚DNA结合亚基内的取代基效应。 通常，在吲哚C5位置的取代导致可以> = 1000倍的细胞毒性效力增强，提供比CBI-TMI，双卡曲霉素SA更有效（IC 50 = 2-3pM）的简单类似物，其包含单个DNA结合亚单位 ，或CC-1065。 细胞毒性的增加与随着DNA烷基化速率和效率的增加有关。 CBI与基于DSA或CPI的类似物相比，这种效应更为明显。 此外，这种效应对C5取代基的电子特性大部分不敏感，但对该取代基的尺寸，刚性长度和形状（sp，sp 2，sp 3杂交）敏感，符合期望的影响 只是因为它的存在。

    ULTRA-POTENT VINA ALKALOIDS: ADDED MOLECULAR COMPLEXITY FURTHER DISRUPTS THE TUBLIN DIMER-DIMER INTERFACE
    5.
    发明申请
    ULTRA-POTENT VINA ALKALOIDS: ADDED MOLECULAR COMPLEXITY FURTHER DISRUPTS THE TUBLIN DIMER-DIMER INTERFACE 审中-公开
    超强力维纳酸生物碱：增加分子复杂性进一步破坏了托林二聚体 - 二聚体界面

    公开(公告)号：WO2017210206A1

    公开(公告)日：2017-12-07

    申请号：PCT/US2017/035027

    申请日：2017-05-30

    Applicant: THE SCRIPPS RESEARCH INSTITUTE

    Inventor： BOGER, Dale, L.

    IPC: C07D487/14 ,  A61K31/437 ,  A61K31/404

    Abstract: Synthetically-derived and previously inaccessible modifications of 20'-hydroxy-vinca derivative compounds such as vinblastine, vincristine or vindesine are disclosed that are a stunning 100-fold more active than the natural product (IC 50 's 50-75 pM vs 7 nM, HCT116), and are now accessible as a result of advances in the total synthesis of the natural product. Illustrative new ultra-potent vinblastines bind tubulin with much higher affinity and likely further disrupt the tubulin head-to-tail α/β dimer-dimer interaction by virtue of the strategic placement of an added conformationally well-defined, rigid and extended C20'-urea along the adjacent protein-protein interface. Added molecular complexity was used to markedly enhance target binding and functional biological activity, and represents a general approach to improving the properties of other natural products targeting a protein-protein interaction. A pharmaceutical composition containing an ultra-potent 20'-hydroxy-vinca derivative compound and a method of treating cancerous cells with such a compound are also disclosed.

    Abstract translation: 公开了20'-羟基 - 长春花衍生化合物例如长春碱，长春新碱或长春地辛的合成衍生的和先前不可接近的修饰，其比天然产物具有惊人的100倍的活性（IC 50的50-75pM vs 7nM，HCT116），并且由于天然产物的总合成的进展而现在可以获得。 说明性的新型超级长春碱以更高的亲和力与微管蛋白结合，并且可能由于添加构象明确的，刚性和延伸的C20'-末端核苷酸的战略位置而进一步破坏微管蛋白头对尾α/β二聚体 - 二聚体相互作用， 尿素沿着相邻的蛋白质 - 蛋白质界面。 增加的分子复杂性被用于显着增强靶结合和功能性生物学活性，并且代表改善靶向蛋白质 - 蛋白质相互作用的其他天然产物的性质的一般方法。 还公开了含有超有效20'-羟基 - 长春花衍生物化合物的药物组合物和用这种化合物治疗癌细胞的方法。

    OXAZOLE KETONES AS MODULATORS OF FATTY ACID AMIDE HYDROLASE
    6.
    发明申请
    OXAZOLE KETONES AS MODULATORS OF FATTY ACID AMIDE HYDROLASE 审中-公开
    奥沙唑酮作为脂肪酸酰胺水解酶的调节剂

    公开(公告)号：WO2007098142A2

    公开(公告)日：2007-08-30

    申请号：PCT/US2007/004341

    申请日：2007-02-20

    Applicant: THE SCRIPPS RESEARCH INSTITUTE ,  BOGER, Dale, L.

    Inventor： BOGER, Dale, L.

    IPC: A61K31/506 ,  A61K31/4439 ,  A61K31/421 ,  C07D413/02

    CPC classification number: C07D263/32 ,  C07D413/04

    Abstract: Certain oxazole ketone compounds are useful as FAAH inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity. Thus, the compounds may be administered to treat anxiety, pain, inflammation, sleep disorders, eating disorders, or movement disorders (such as MS).

    Abstract translation: 某些恶唑酮化合物可用作FAAH抑制剂。 此类化合物可用于治疗由脂肪酰胺水解酶（FAAH）活性介导的疾病状态，病症和病症的药物组合物和方法。 因此，可以施用化合物以治疗焦虑，疼痛，炎症，睡眠障碍，进食障碍或运动障碍（例如MS）。

    INHIBITORS OF FATTY ACID AMIDE HYDROLASE
    7.
    发明申请
    INHIBITORS OF FATTY ACID AMIDE HYDROLASE 审中-公开

    公开(公告)号：WO2004033652A3

    公开(公告)日：2004-04-22

    申请号：PCT/US2003/031975

    申请日：2003-10-08

    Applicant: THE SCRIPPS RESEARCH INSTITUTE ,  BOGER, Dale, L.

    Inventor： BOGER, Dale, L.

    IPC: C07D277/20

    Abstract: Improved competitive inhibitors of FAAH employ an α-keto heterocyclic pharmacophore and a binding subunit having a ?-unsaturation. The α-keto heterocyclic pharmacophore and a binding subunit are attached to one another, preferably by a hydrocarbon chain. The improvement lies in the use of a heterocyclic pharmacophore selected from oxazoles, oxadiazoles, thiazoles, and thiadiazoles that have alkyl or aryl substituents at their 4 and/or 5 positions. The improved competitive inhibitors of FAAH display enhanced activity over conventional competitive inhibitors of FAAH.

    DIPROVOCIMS: A NEW AND POTENT CLASS OF TLR AGONISTS
    8.
    发明申请
    DIPROVOCIMS: A NEW AND POTENT CLASS OF TLR AGONISTS 审中-公开
    DIPROVOCIMS：一种全新而有力的TLR激进分子

    公开(公告)号：WO2018005812A1

    公开(公告)日：2018-01-04

    申请号：PCT/US2017/040028

    申请日：2017-06-29

    Applicant: THE SCRIPPS RESEARCH INSTITUTE ,  THE BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM ,  BEUTLER, Bruce ,  BOGER, Dale, L.

    Inventor： BEUTLER, Bruce ,  BOGER, Dale, L.

    IPC: C07D403/10 ,  A61K31/40 ,  A61K31/4025

    Abstract: A diprovocim compound that corresponds in structure to structural Formula V is disclosed, wherein A, W, Z, R 1 , R 2 , R 3 and R 4 (when present) are defined within. A diprovocim compound has immune-adjuvant properties on human and mouse cells in culture and on in vivo immunization of mice. A composition containing a diprovocim and a method of using a compound are also disclosed. The immunostimulatory activity of a diprovocim compound is similar to that of LPS, to which there is no apparent structural similarity. A contemplated compound bears no structural similarity to either the TLR1/TLR2 lipoprotein agonists nor to any other synthetic TLR agonist, and is remarkably easy to prepare and synthetically modify.

    Abstract translation: 在结构上对应于结构式V的diprovocim化合物被公开，其中A，W，Z，R 1，R 2，R，R 3， 3和R 4（当存在时）在内部定义。 浸渍化合物对培养的人和小鼠细胞和小鼠的体内免疫具有免疫佐剂性质。 还公开了含有浸药的组合物和使用化合物的方法。 diprovocim化合物的免疫刺激活性与LPS相似，没有明显的结构相似性。 所考虑的化合物与TLR1 / TLR2脂蛋白激动剂或任何其他合成TLR激动剂不具有结构相似性，并且非常易于制备和合成修饰。

    N- (HYDROPHOBE-SUBSTITUTED) VANCOSAMINYL [Ψ[C(=NH) NH] TPG4] VANCOMYCIN AND [Ψ[CH2NH]TPG4] VANCOMYCIN
    10.
    发明申请
    N- (HYDROPHOBE-SUBSTITUTED) VANCOSAMINYL [Ψ[C(=NH) NH] TPG4] VANCOMYCIN AND [Ψ[CH2NH]TPG4] VANCOMYCIN 审中-公开
    N-（取代羟基取代的）VANCOSAMINYL [Ψ[C（= NH）NH] TPG4] VANCOMYCIN和[Ψ[CH2NH] TPG4] VANCOMYCIN

    公开(公告)号：WO2016007855A1

    公开(公告)日：2016-01-14

    申请号：PCT/US2015/039942

    申请日：2015-07-10

    Applicant: THE SCRIPPS RESEARCH INSTITUTE

    Inventor： BOGER, Dale, L.

    IPC: C07K9/00 ,  A61K38/14 ,  A61P31/04

    CPC classification number: C07K9/008 ,  A61K38/00

    Abstract: The total synthesis and evaluation of key analogs of vancomycin containing single atom changes in the binding pocket are disclosed as well as their peripherally modified, N- (hydrophobe-substituted) derivatives exemplified by a N-4- ( 4 ' -chlorobiphenyl) - methyl derivative and their pharmaceutically acceptable salts are disclosed. Their evaluation indicates the combined pocket and peripherally modified analogs exhibit a remarkable spectrum of antimicrobial activity and truly impressive potencies against both vancomycin-sensitive and -resistant bacteria, and likely benefit from two independent and synergistic mechanisms of action. A pharmaceutical composition containing a contemplated compound or its pharmaceutically acceptable salt is disclosed, as is a method of treating a bacterial infection in a mammal by administering an antibacterial amount of a contemplated compound or its salt as above to an infected mammal in need of treatment.

    Abstract translation: 公开了在结合口袋中含有单原子变化的万古霉素的关键类似物的总合成和评价以及它们的外周修饰的N-（疏水取代的）衍生物，例如N-4-（4'-氯联苯基） - 甲基 衍生物及其药学上可接受的盐。 他们的评估表明组合口袋和外围修饰的类似物表现出显着的抗微生物活性谱，并且对万古霉素敏感和抗性细菌都具有真正令人印象深刻的效力，并且可能受益于两种独立和协同作用机制。 公开了包含预期化合物或其药学上可接受的盐的药物组合物，以及通过向需要治疗的受感染哺乳动物施用抗菌剂量的预期化合物或其盐来治疗哺乳动物细菌感染的方法。

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