公开(公告)号：US20110201686A1

公开(公告)日：2011-08-18

申请号：US12308475

申请日：2007-06-22

Applicant: Yousef Al-Abed

Inventor： Yousef Al-Abed

IPC: A61K31/167 ,  A61P25/28 ,  C12N5/02

CPC classification number: A61K31/165

Abstract: Provided are methods of inhibiting aggregation of amyloid-beta (Aβ) or accumulation of aggregated Aβ using certain guanylhydrazone compounds. Also provided are methods of treating or preventing an amyloid-related disease in a mammal, methods of treating a subject having Alzheimer's disease, methods of treating a subject at risk for Alzheimer's disease, methods of inhibiting aggregation or accumulation of a synuclein, methods of treating a subject having a disease at least partially mediated by synuclein, methods of treating a subject at risk for a disease at least partially mediated by synuclein, and methods of inhibiting aggregation or accumulation of a protein involved in a conformational disease, using the guanylhydrazone compounds.

Abstract translation: 提供了抑制淀粉样蛋白β（A和Bgr）聚集或聚集的A＆Bgr的积累的方法。 使用某些脒腙化合物。 还提供了治疗或预防哺乳动物的淀粉样蛋白相关疾病的方法，治疗患有阿尔茨海默病的受试者的方法，治疗患有阿尔茨海默病风险的受试者的方法，抑制突触核蛋白的聚集或积累的方法，治疗方法 具有至少部分由突触核蛋白介导的疾病的受试者，使用脒腙化合物治疗至少部分由突触核蛋白介导的疾病风险的受试者的方法和参与构象疾病的蛋白质的聚集或积聚的方法。

公开(公告)号：US20110195939A1

公开(公告)日：2011-08-11

申请号：US13056696

申请日：2009-07-30

Applicant: Ferdinando Nicoletti ,  Yousef Al-Abed ,  Gianni Garotta

Inventor： Ferdinando Nicoletti ,  Yousef Al-Abed ,  Gianni Garotta

IPC: A61K31/635 ,  C07D401/12 ,  A61K31/4725 ,  C07D217/26 ,  C07D401/06 ,  A61K31/496 ,  C07D239/10 ,  A61K31/513 ,  C07D307/20 ,  C07D213/56 ,  A61K31/4418 ,  A61P31/18 ,  A61P35/00

CPC classification number: A61K31/00 ,  A61K31/4725 ,  C07D401/12

Abstract: HIV-protease inhibitors, particularly saquinavir, showed strong anticancer activity but numerous side effects limited its application. In order to overcome its toxicity original compounds were modified by covalent attachment of NO. The efficacy of parental and NO-modified drug was compared in vitro and in vivo. Anticancer activities of NO-modified saquinavir (Saq-NO) was monitored in vitro using assay for cell viability, proliferation, necrotic, autophagic and apoptotic cell death, differentiation, expression of intracellular molecules such as cyclin D3, p53 and Akt. Antitumor properties and toxicity of the compound was estimated in vivo. Saq-NO abrogated the viability of large spectrum of human and rodent tumor cell lines with IC50 significantly lower than parental drug and expressed strong antimelanoma action in vivo. In contrast to saquinavir, there was no detectable toxicity against primary cells in vitro and in vivo. Saq-NO permanently diminished cell proliferation by induction of cell cycle block accompanied with minor presence of tumor cell death. Repressed proliferation was coordinated with strong activation of p53 and differentiation of C6 and B16 cells into oligodendrocytes or “Schwan” like cells, respectively. Oppositely to general characteristic of saquinavir to inhibit Akt signalling, Saq-NO treatment resulted in transient and intensive upregulation of Akt. This antagonism between parental and modified compound could be the crucial for switch of saquinavir from toxic to completely untoxic drug.

Abstract translation: HIV-蛋白酶抑制剂，特别是沙奎那韦，表现出很强的抗癌活性，但许多副作用限制了其应用。 为了克服其毒性，原始化合物通过NO的共价连接进行修饰。 在体外和体内比较了亲本和NO-修饰药物的功效。 通过测定细胞活力，增殖，坏死，自噬和凋亡细胞死亡，分化，细胞周期蛋白D3，p53和Akt等细胞内分子的表达，体外监测NO-修饰的沙奎那韦（Saq-NO）的抗癌活性。 在体内估计化合物的抗肿瘤性质和毒性。 Saq-NO消除了大量人和啮齿类动物肿瘤细胞系的活力，其IC50明显低于亲本药物，并在体内表达强烈的抗血管瘤作用。 与沙奎那韦相比，在体外和体内对原代细胞没有可检测的毒性。 Saq-NO通过诱导细胞周期阻滞而持续减少细胞增殖，伴随肿瘤细胞死亡的轻微存在。 抑制增殖与p53的强活化和C6和B16细胞分化为少突胶质细胞或“Schwan”样细胞分别协调。 与沙奎那韦抑制Akt信号的一般特征相反，Saq-NO处理导致Akt的瞬时和强化上调。 父母和修饰化合物之间的这种拮抗作用可能是将沙奎那韦从毒性转变为完全无毒的药物至关重要的。

公开(公告)号：US20110015231A1

公开(公告)日：2011-01-20

申请号：US12891447

申请日：2010-09-27

Applicant: Yousef Al-Abed ,  Kevin J. Tracey

Inventor： Yousef Al-Abed ,  Kevin J. Tracey

IPC: A61K31/444 ,  A61P29/00 ,  A61P11/06 ,  A61P11/08 ,  A61P31/00 ,  A61P31/18 ,  A61P25/28

CPC classification number: C07D413/14 ,  C07D413/04

Abstract: Compounds of Formula (I), pharmaceutical compositions comprising compounds of Formulae (I a) or (VII) and a method of treating a subject with an inflammatory cytokine-mediated disorder comprising administering to the subject a compound of Formulae (I a) or (VIIa). The variables of Formulae (I), (I a), (VII) and (VII a) are described herein.

Abstract translation: 式（I）的化合物，包含式（Ia）或（VII）的化合物的药物组合物和用炎性细胞因子介导的病症治疗受试者的方法，其包括向受试者施用式（Ia）或（ VIIa）。 本文描述了式（I），（Ia），（VII）和（VIIa）的变量。

公开(公告)号：US20100305176A1

公开(公告)日：2010-12-02

申请号：US12599221

申请日：2008-05-06

Applicant: Ferdinando Nicoletti ,  Yousef Al-Abed ,  Gianni Garotta

Inventor： Ferdinando Nicoletti ,  Yousef Al-Abed ,  Gianni Garotta

IPC: A61K31/422 ,  C07D413/12 ,  A61P35/00 ,  A61P29/00 ,  A61P1/16 ,  A61P1/04

CPC classification number: C07D413/12

Abstract: The present invention relates to an isoxazole derivative, the compound of formula (I) herein after referred to as GIT27-NO, which is the NO-donating structurally modified form of (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid, herein after referred to as VGX-1027.Treatment of three tumor cell lines, rat astrocytoma C6, mouse fibrosarcoma L929, and mouse melanoma B16 cells with GIT27-NO resulted in a significant reduction of cell respiration and of number of viable cells, while VGX-1027 was completely ineffective. Hemoglobin, which act as NO-scavenger, restored cell viability, thus indicating the NO-mediated tumoricidal effect of compound (I). GIT27-NO triggered apoptotic cell death in L929 cell cultures, while autophagic cell death is mainly responsible for the diminished viability of C6 and B16 cells. Moreover, GIT27-NO induced the production of reactive oxygen species which can be neutralized by antioxidant N-acetyl cysteine (NAC), indicating that reactive oxygen species (ROS) are at least partly involved in the reduction of cell viability. The anti-tumor activity of GIT27-NO is mediated through activation of MAP kinases (ERK1/2, p38 and JNK) in cell-specific manner. The role of MAP kinases was further confirmed by specific inhibitors of these molecules, PD98059, SB202190, and SP600125. Finally, in vivo treatment with GIT27-NO significantly reduced tumor growth in syngeneic C57BL/6 mice implanted with B16 melanoma.

Abstract translation: 本发明涉及异恶唑衍生物，本文的式（I）化合物在本文中称为GIT27-NO，其是（S，R）-3-苯基-4,5-二氢的NO供体结构修饰形式 -5-异恶唑乙酸，此后称为VGX-1027。 用GIT27-NO处理三种肿瘤细胞系，大鼠星形细胞瘤C6，小鼠纤维肉瘤L929和小鼠黑素瘤B16细胞导致细胞呼吸和活细胞数量的显着降低，而VGX-1027完全无效。 作为NO清除剂的血红蛋白恢复细胞活力，从而表明化合物（I）的NO介导的杀肿瘤作用。 GIT27-NO在L929细胞培养物中引发凋亡细胞死亡，而自噬细胞死亡主要是C6和B16细胞活力下降的主要原因。 此外，GIT27-NO诱导可被抗氧化剂N-乙酰半胱氨酸（NAC）中和的活性氧的产生，表明活性氧（ROS）至少部分参与细胞活力的降低。 GIT27-NO的抗肿瘤活性通过以细胞特异性方式激活MAP激酶（ERK1 / 2，p38和JNK）介导。 MAP激酶的作用由这些分子PD98059，SB202190和SP600125的特异性抑制剂进一步证实。 最后，使用GIT27-NO的体内治疗显着降低植入B16黑素瘤的同基因C57BL / 6小鼠的肿瘤生长。

公开(公告)号：US07662843B2

公开(公告)日：2010-02-16

申请号：US10828240

申请日：2004-04-21

Applicant: Yousef Al-Abed

Inventor： Yousef Al-Abed

IPC: A01N43/80 ,  C07D261/02

CPC classification number: A61K31/421 ,  C07D261/04

Abstract: Methods of use and pharmaceutical compositions for a genus of low molecular weight compounds comprising optionally substituted isoxazoline ring systems that act as inhibitors of MIF (macrophage migration inhibitory factor) are disclosed. Specifically, the compounds are useful for treating a variety of diseases involving inflammatory activity or pro-inflammatory cytokine responses, such as autoimmune diseases (including rheumatiod arthritis, insulin-dependent diabetes, multiple sclerosis, graft versus host disease, lupus syndromes), asthma, arthritis, ARDS, psoriasis, interleukin-2 toxicity, proliferative vascular disease, and various forms of sepsis and septic shock, and other conditions characterized by underlying MIF responses including, for instance, tumor growth and neovascularization (angiogenesis).

Abstract translation: 公开了用作低分子量化合物的药物组合物的方法，其包含用作MIF抑制剂（巨噬细胞迁移抑制因子）的任选取代的异恶唑啉环体系。 具体地说，该化合物可用于治疗涉及炎症活性或促炎细胞因子应答的各种疾病，例如自身免疫性疾病（包括风湿性关节炎，胰岛素依赖性糖尿病，多发性硬化，移植物抗宿主病，狼疮综合征），哮喘， 关节炎，ARDS，牛皮癣，白细胞介素-2毒性，增殖性血管疾病和各种形式的败血症和败血性休克，以及其他基本MIF反应特征的病症，包括例如肿瘤生长和新生血管形成（血管生成）。

公开(公告)号：US20100016391A1

公开(公告)日：2010-01-21

申请号：US12360290

申请日：2009-01-27

Applicant: Yousef Al-Abed

Inventor： Yousef Al-Abed

IPC: A61K31/42 ,  A61P29/00

CPC classification number: A61K31/421 ,  C07D261/04

Abstract: Methods of use and pharmaceutical compositions for a genus of low molecular weight compounds comprising optionally substituted isoxazoline ring systems that act as inhibitors of MIF (macrophage migration inhibitory factor) are disclosed. Specifically, the compounds are useful for treating a variety of diseases involving inflammatory activity or pro-inflammatory cytokine responses, such as autoimmune diseases (including rheumatoid arthritis, insulin-dependent diabetes, multiple sclerosis, graft versus host disease, lupus syndromes), asthma, arthritis, ARDS, psoriasis, interleukin-2 toxicity, proliferative vascular disease, and various forms of sepsis and septic shock, and other conditions characterized by underlying MIF responses including, for instance, tumor growth and neovascularization (angiogenesis).

Abstract translation: 公开了用作低分子量化合物的药物组合物的方法，其包含用作MIF抑制剂（巨噬细胞迁移抑制因子）的任选取代的异恶唑啉环体系。 具体地说，该化合物可用于治疗涉及炎症活性或促炎细胞因子应答的各种疾病，例如自身免疫性疾病（包括类风湿性关节炎，胰岛素依赖性糖尿病，多发性硬化，移植物抗宿主病，狼疮综合征），哮喘， 关节炎，ARDS，牛皮癣，白细胞介素-2毒性，增殖性血管疾病和各种形式的败血症和败血性休克，以及其他基本MIF反应特征的病症，包括例如肿瘤生长和新生血管形成（血管生成）。

公开(公告)号：US06538131B1

公开(公告)日：2003-03-25

申请号：US09556147

申请日：2000-04-19

Applicant: Yousef Al-Abed ,  Mohindra Seepersaud

Inventor： Yousef Al-Abed ,  Mohindra Seepersaud

IPC: C07G1700

CPC classification number: C07H1/00 ,  C07C29/132 ,  C07C43/188 ,  C07C45/29 ,  C07C45/49 ,  C07C45/78 ,  C07C49/597 ,  C07C2601/10 ,  C07C49/255 ,  C07C49/753 ,  C07C31/205 ,  C07C31/274 ,  C07C31/276

Abstract: Chemical processes for more efficient synthesis of carbocyclic polyols and substituted sugar analogs are disclosed, together with a novel class of cyclopentene polyol intermediate products and anhydro derivatives thereof.

Abstract translation: 公开了用于更有效地合成碳环多元醇和取代的糖类似物的化学方法，以及一类新型的环戊烯多元醇中间体产物及其脱水衍生物。

公开(公告)号：US06492428B1

公开(公告)日：2002-12-10

申请号：US09625829

申请日：2000-07-26

Applicant: Yousef Al-Abed ,  Richard J. Bucala ,  Robert A. Mitchell ,  Peter Senter

Inventor： Yousef Al-Abed ,  Richard J. Bucala ,  Robert A. Mitchell ,  Peter Senter

IPC: A61K3117

CPC classification number: A61K31/122 ,  A61K31/167

Abstract: There are disclosed methods of use and pharmaceutical compositions for two related genera of low molecular weight compounds comprising optionally substituted iminoquinone or orthoquinone ring systems. The compounds have MIF (macrophage migration inhibitory factor) antagonist activity and find utility as such. For example, the compounds are useful for treating a variety of diseases involving inflammatory activity or pro-inflammatory cytokine responses, such as autoimmune diseases (including rheumatiod arthritis, insulin-dependent diabetes, multiple sclerosis, graft versus host disease, lupus syndromes), asthma, arthritis, EAE, ARDS, psoriasis, interleukin-2 toxicity, proliferative vascular disease, and various forms of sepsis and septic shock, and other conditions characterized by underlying MIF responses including, for instance, tumor growth and neovascularization (angiogenesis).

Abstract translation: 公开了使用的方法和用于两种相关属的低分子量化合物的药物组合物，其包含任选取代的亚氨基醌或正醌环系。 这些化合物具有MIF（巨噬细胞迁移抑制因子）拮抗剂活性，并发现其效用。 例如，该化合物可用于治疗涉及炎症活性或促炎细胞因子应答的各种疾病，例如自身免疫疾病（包括风湿性关节炎，胰岛素依赖性糖尿病，多发性硬化，移植物抗宿主病，狼疮综合征），哮喘 ，关节炎，EAE，ARDS，牛皮癣，白细胞介素-2毒性，增殖性血管疾病和各种形式的败血症和败血性休克，以及其他由潜在的MIF反应（包括例如肿瘤生长和新生血管形成）（血管发生）表征的病症。

公开(公告)号：US06380165B1

公开(公告)日：2002-04-30

申请号：US08933655

申请日：1997-09-19

Applicant: Yousef Al-Abed ,  Richard J. Bucala

Inventor： Yousef Al-Abed ,  Richard J. Bucala

IPC: A61K3800

CPC classification number: G01N33/6842 ,  G01N33/68 ,  G01N33/6893

Abstract: There is disclosed a means for standardizing a kit that provides a means for measuring the formation of advanced glycosylation endproducts (AGEs). The present invention further provides a novel isolate AGE that is antigenic and useful for forming antibodies having utility in diagnostic assays and for standardizing diagnostic assays.

Abstract translation: 公开了一种标准化试剂盒的方法，该试剂盒提供了测量高级糖基化终产物（AGE）形成的方法。 本发明还提供了一种新型的分离AGE，其是抗原性的并且可用于形成在诊断测定中具有效用的抗体并用于标准化诊断测定。