公开(公告)号：US06218128B1

公开(公告)日：2001-04-17

申请号：US09042943

申请日：1998-03-17

申请人： Elliott S. Klein ,  Sunil Nagpal ,  Roshantha A. Chandraratna

发明人： Elliott S. Klein ,  Sunil Nagpal ,  Roshantha A. Chandraratna

IPC分类号： G01N3353

CPC分类号： G01N33/566 ,  G01N2333/70567 ,  G01N2500/00

摘要： Methods of characterizing and identifying negative hormones of nuclear receptors. Also disclosed are methods of making modulators of retinoid nuclear receptor transactivation activity, assays for agonists, antagonists, and negative hormones of the RAR receptor, and specific retinoid modulators of retinoid nuclear receptors.

摘要翻译： 表征和鉴定核受体负激素的方法。 还公开了制备类视黄醇核受体反式激活活性的调节剂的方法，RAR受体的激动剂，拮抗剂和负激素的测定，以及类视黄醇核受体的特异性维甲酸调节剂。

公开(公告)号：US6071924A

公开(公告)日：2000-06-06

申请号：US175192

申请日：1998-10-20

申请人： Peter A. Campochiaro ,  Larry A. Wheeler ,  Roshantha A. Chandraratna ,  Sunil Nagpal

发明人： Peter A. Campochiaro ,  Larry A. Wheeler ,  Roshantha A. Chandraratna ,  Sunil Nagpal

IPC分类号： A61K9/127 ,  A61K9/14 ,  A61K31/19 ,  A61K31/192 ,  A61K31/455 ,  A61K31/465 ,  A61K45/00 ,  A61K47/24 ,  A61P27/02 ,  A61P35/00 ,  A61K31/435

CPC分类号： A61K31/455 ,  A61K31/192 ,  Y10S514/912

摘要： Proliferation of retinal pigment epithelium following surgery or trauma is prevented by contacting retinal pigment epithelium cells with a therapeutic amount of a retinoic acid receptor (RAR) agonist, preferably one with specific activity for retinoic acid receptors. Preferably the RAR agonist is also a potent antagonist of AP1-dependent gene expression. Alternatively, the proliferation of retinal pigment epitelium is ameliorated with a therapeutic amount of an AP-1 antagonist, alone or in combination with an RAR agonist. The drug can be administered by bolus injection into the vitreous cavity using a dosage from about 50 to 150 .mu.g, or by slow release from liposomes or an oil tamponade injected into the vitreous cavity. Formulations for preventing proliferation of retinal pigment epithelium are also provided.

摘要翻译： 通过使视网膜色素上皮细胞与治疗量的视黄酸受体（RAR）激动剂接触，优选对视黄酸受体具有特异性活性的那些激动剂来防止手术或创伤后视网膜色素上皮的增殖。 优选地，RAR激动剂也是AP1依赖性基因表达的有效拮抗剂。 或者，视网膜色素上皮的增殖用治疗量的AP-1拮抗剂单独或与RAR激动剂组合改善。 药物可以通过使用约50至150μg的剂量或通过从注射到玻璃体腔中的脂质体或油栓塞缓慢释放而推注到玻璃体腔中来施用。 还提供了用于防止视网膜色素上皮细胞增殖的制剂。

公开(公告)号：US06573271B2

公开(公告)日：2003-06-03

申请号：US09954686

申请日：2001-09-11

申请人： Peter A. Campochiaro ,  Larry A. Wheeler ,  Roshantha A. Chandraratna ,  Sunil Nagpal ,  Eugene De Juan, Jr.

发明人： Peter A. Campochiaro ,  Larry A. Wheeler ,  Roshantha A. Chandraratna ,  Sunil Nagpal ,  Eugene De Juan, Jr.

IPC分类号： A61K31435

CPC分类号： A61K31/455 ,  A61K31/192 ,  Y10S514/912

摘要： Proliferation of retinal pigment epithelium following surgery or trauma or resulting in ocular diseases associated with choroidal neovascularization, such as age related macular degeneration and histoplasmosis syndrome, is prevented by contacting retinal pigment epithelium cells with a therapeutic amount of a retinoic acid receptor (RAR agonist, preferably one with specific activity for retinoic acid receptors. Preferably the RAR agonist is also a potent antagonist of AP1-dependent gene expression. Alternatively, the proliferation of retinal pigment epithelium is ameliorated with a therapeutic amount of an AP-1 antagonist, alone or in combination with an RAR agonist. The drug can be administered by bolus injection into the vitreous cavity using a dosage from about 50 to 150 &mgr;g. Or by slow release from liposomes or an oil tamponade injected into the vitreous cavity. Formulations for preventing proliferation of retinal pigment epithelium are also provided.

公开(公告)号：US5650279A

公开(公告)日：1997-07-22

申请号：US379280

申请日：1995-01-27

申请人： Sunil Nagpal ,  Roshantha A. Chandraratna

发明人： Sunil Nagpal ,  Roshantha A. Chandraratna

IPC分类号： C07K14/705 ,  C12N15/12 ,  C12Q1/68 ,  C07H21/02 ,  C07H21/04 ,  C12P19/34

CPC分类号： C07K14/705 ,  C12Q1/6883 ,  C12Q2600/136 ,  C12Q2600/158

摘要： One aspect of the invention relates to a novel human cDNA, called TIG1 (Tazarotene Induced Gene 1). Expression of the corresponding TIG1 mRNA is strongly induced from a low basal level upon treatment of skin raft cultures with the RAR .beta./.gamma. selective anti-psoriatic synthetic retinoid AGN-190168 (ethyl 6-[2-(4,4) dimethyl-thiochroman-6-yl] ethynyl-nicotinate). The TIG1 mRNA is also up-regulated by AGN-190168 and the acid form AGN-190299 (6-[2-(4,4) dimethyl-thiochroman-6-yl] ethynyl-nicotinic acid) in skin raft cultures prepared from psoriatic fibroblasts and normal keratinocytes. Further, the TIG1 mRNA is similarly up-regulated by AGN-190168 in primary fibroblast and keratinocyte cultures. The low basal expression of the TIG1 mRNA is particularly advantageous when used as an indicator of retinoid action in psoriatic skin culture systems. Assay systems employing this unique TIG1 expression profile are disclosed.

摘要翻译： 本发明的一个方面涉及一种称为TIG1（他扎罗汀诱导的基因1）的新型人cDNA。 用RARβ/γ选择性抗牛皮癣合成类视黄醇AGN-190168（6- [2-（4,4）二甲基 - 二氢苯并噻喃-2-基）苯甲酸处理皮肤筏培养物时，从低的基础水平强烈诱导相应的TIG1 mRNA的表达 -6-基]乙炔基 - 烟酸酯）。 TIG1 mRNA也由AGN-190168和酸性形式AGN-190299（6- [2-（4,4）二甲基 - 二氢苯并噻喃-6-基]乙炔基 - 烟酸）在由牛皮癣制备的皮肤筏培养物中上调 成纤维细胞和正常角质形成细胞。 此外，TIG1 mRNA在原代成纤维细胞和角质细胞培养物中类似地被AGN-190168上调。 当用作银屑病皮肤培养系统中类视黄醇作用的指标时，TIG1 mRNA的低基础表达是特别有利的。 公开了采用这种独特的TIG1表达谱的测定系统。

公开(公告)号：US06942980B1

公开(公告)日：2005-09-13

申请号：US09685828

申请日：2000-10-10

申请人： Elliott S. Klein ,  Sunil Nagpal ,  Roshantha A. Chandraratna

发明人： Elliott S. Klein ,  Sunil Nagpal ,  Roshantha A. Chandraratna

IPC分类号： C12Q1/68

CPC分类号： C12Q1/6897 ,  G01N2333/70567 ,  G01N2500/04

摘要： Methods of characterizing and identifying negative hormones of nuclear receptors. Also disclosed are methods of making modulators of retinoid nuclear receptor transactivation activity, assays for agonists, antagonists, and negative hormones of the RAR receptor, and specific retinoid modulators of retinoid nuclear receptors.

摘要翻译： 表征和鉴定核受体负激素的方法。 还公开了制备类视黄醇核受体反式激活活性的调节剂的方法，RAR受体的激动剂，拮抗剂和负激素的测定，以及类视黄醇核受体的特异性维甲酸调节剂。

公开(公告)号：US06294657B1

公开(公告)日：2001-09-25

申请号：US08996533

申请日：1997-12-23

申请人： Sunil Nagpal ,  Daniel DiSepio ,  Roshantha A. Chandraratna

发明人： Sunil Nagpal ,  Daniel DiSepio ,  Roshantha A. Chandraratna

IPC分类号： C07H2102

CPC分类号： C07K14/82

摘要： A novel human cDNA, called TIG3 (Tazarotene Induced Gene 3), inducible by RAR-selective retinoids and structurally related to a known tumor suppressor gene. Methods of detecting the TIG3 polynucleotide.

摘要翻译： 一种称为TIG3（他扎罗汀诱导的基因3）的新型人类cDNA，由RAR选择性类维生素A诱导，并与已知的肿瘤抑制基因结构相关。 检测TIG3多核苷酸的方法。

公开(公告)号：US6075032A

公开(公告)日：2000-06-13

申请号：US875665

申请日：1998-01-23

申请人： Peter A. Campochiaro ,  Larry A. Wheeler ,  Roshantha A. Chandraratna ,  Sunil Nagpal ,  Eugene De Juan, Jr.

发明人： Peter A. Campochiaro ,  Larry A. Wheeler ,  Roshantha A. Chandraratna ,  Sunil Nagpal ,  Eugene De Juan, Jr.

IPC分类号： A61K9/127 ,  A61K9/14 ,  A61K31/19 ,  A61K31/192 ,  A61K31/455 ,  A61K31/465 ,  A61K45/00 ,  A61K47/24 ,  A61P27/02 ,  A61P35/00 ,  A61K31/435 ,  A61K31/07

CPC分类号： A61K31/455 ,  A61K31/192 ,  Y10S514/912

摘要： Proliferation of retinal pigment epithelium following surgery or trauma or resulting in ocular diseases associated with choroidal neovascularization, such as age related macular degeneration and histoplasmosis syndrome, is prevented by contacting retinal pigment epithelium cells with a therapeutic amount of a retinoic acid receptor (RAR agonist, preferably one with specific activity for retinoic acid receptors. Preferably the RAR agonist is also a potent antagonist of AP1-dependent gene expression. Alternatively, the proliferation of retinal pigment epithelium is ameliorated with a therapeutic amount of an AP-1 antagonist, alone or in combination with an RAR agonist. The drug can be administered by bolus injection into the vitreous cavity using a dosage from about 50 to 150 .mu.g. Or by slow release from liposomes or an oil tamponade injected into the vitreous cavity. Formulations for preventing proliferation of retinal pigment epithelium are also provided.

摘要翻译： PCT No.PCT / US96 / 01505 Sec。 371日期1998年1月23日 102（e）日期1998年1月23日PCT提交1996年1月31日PCT公布。 公开号WO96 / 23498 日期1996年8月8日通过使视网膜色素上皮细胞与治疗量的视黄酸接触来预防手术或创伤后视网膜色素上皮细胞增生或与脉络膜新生血管形成相关的眼部疾病，如年龄相关性黄斑变性和组织胞浆菌病综合征 受体（RAR激动剂，优选具有对视黄酸受体具有比活性的激动剂），优选地，RAR激动剂也是AP1依赖性基因表达的有效拮抗剂，或者，用治疗量的AP-1改善视网膜色素上皮的增殖 拮抗剂，单独或与RAR激动剂组合，药物可以通过使用约50至150μg的剂量通过快速注射进入玻璃体腔中，或通过从脂质体缓慢释放或注入玻璃体腔的油栓塞来施用。 还提供了用于防止视网膜色素上皮细胞增殖的制剂。

公开(公告)号：US06372753B1

公开(公告)日：2002-04-16

申请号：US09536221

申请日：2000-03-27

申请人： Peter A. Campochiaro ,  Larry A. Wheeler ,  Roshantha A. Chandraratna ,  Sunil Nagpal ,  Eugene De Juan, Jr.

发明人： Peter A. Campochiaro ,  Larry A. Wheeler ,  Roshantha A. Chandraratna ,  Sunil Nagpal ,  Eugene De Juan, Jr.

IPC分类号： A61K31435

CPC分类号： A61K31/455 ,  A61K31/192 ,  Y10S514/912

摘要： Proliferation of retinal pigment epithelium following surgery or trauma or resulting in ocular diseases associated with choroidal neovascularization, such as age related macular degeneration and histoplasmosis syndrome, is prevented by contacting retinal pigment epithelium cells with a therapeutic amount of a retinoic acid receptor (RAR agonist, preferably one with specific activity for retinoic acid receptors. Preferably the RAR agonist is also a potent antagonist of AP1-dependent gene expression. Alternatively, the proliferation of retinal pigment epithelium is ameliorated with a therapeutic amount of an AP-1 antagonist, alone or in combination with an RAR agonist. The drug can be administered by bolus injection into the vitreous cavity using a dosage from about 50 to 150 &mgr;g. Or by slow release from liposomes or an oil tamponade injected into the vitreous cavity. Formulations for preventing proliferation of retinal pigment epithelium are also provided.

摘要翻译： 通过使视网膜色素上皮细胞与治疗量的视黄酸受体（RAR激动剂，血管内皮细胞生长因子受体）接触，可防止手术或外伤后视网膜色素上皮细胞增生，或导致与脉络膜新生血管形成相关的眼部疾病，如年龄相关性黄斑变性和组织胞浆菌病综合征 优选地，具有比较活性的视黄酸受体，优选地，RAR激动剂也是AP1依赖性基因表达的有效拮抗剂，或者，视网膜色素上皮的增殖用治疗量的AP-1拮抗剂单独或在 与RAR激动剂组合，药物可以通过使用约50至150杯的剂量通过快速注射进入玻璃体腔，或通过从脂质体缓慢释放或注射到玻璃体腔中的油脂填充剂来制备。用于防止视网膜增殖的制剂 还提供了色素上皮。

公开(公告)号：US5776699A

公开(公告)日：1998-07-07

申请号：US613863

申请日：1996-03-11

申请人： Elliott S. Klein ,  Sunil Nagpal ,  Roshantha A. Chandraratna

发明人： Elliott S. Klein ,  Sunil Nagpal ,  Roshantha A. Chandraratna

IPC分类号： C07D317/26 ,  A61K31/15 ,  A61K31/192 ,  A61K31/215 ,  A61K31/216 ,  A61K31/341 ,  A61K31/352 ,  A61K31/357 ,  A61K31/37 ,  A61K31/381 ,  A61K31/382 ,  A61K31/426 ,  A61K31/44 ,  A61K31/4402 ,  A61K31/4406 ,  A61K31/4418 ,  A61K31/47 ,  A61K38/09 ,  A61P5/00 ,  A61P39/02 ,  C07C20060101 ,  C07C57/50 ,  C07C63/33 ,  C07C63/331 ,  C07C63/49 ,  C07C63/66 ,  C07C63/72 ,  C07C63/74 ,  C07C65/19 ,  C07C65/28 ,  C07C65/38 ,  C07C69/48 ,  C07C69/618 ,  C07C69/76 ,  C07C69/773 ,  C07C69/90 ,  C07C69/94 ,  C07C233/81 ,  C07C245/10 ,  C07C327/48 ,  C07C335/06 ,  C07C403/20 ,  C07D20060101 ,  C07D213/55 ,  C07D215/12 ,  C07D277/20 ,  C07D277/30 ,  C07D307/54 ,  C07D311/58 ,  C07D333/24 ,  C07D335/06 ,  C07F7/08 ,  G01N33/567

CPC分类号： C07D335/06 ,  C07C233/81 ,  C07C245/10 ,  C07C327/48 ,  C07C57/50 ,  C07C63/33 ,  C07C63/49 ,  C07C63/66 ,  C07C63/72 ,  C07C63/74 ,  C07C65/19 ,  C07C65/28 ,  C07C65/38 ,  C07C69/618 ,  C07C69/76 ,  C07C69/90 ,  C07C69/94 ,  C07D213/55 ,  C07D277/30 ,  C07D307/54 ,  C07D333/24 ,  C07F7/0818 ,  C07C2102/10

摘要： Aryl-substituted and aryl and (3-oxo-1-propenly)-substituted benzopyran, benzothiopyran, 1,2-dihydroquinoline, and 5,6-dihydronaphthalene derivatives have retinoid negative hormone and/or antagonist-like biological activities. The invented RAR antagonists can be administered to mammals, including humans, for the purpose of preventing or diminishing action of RAR agonists on the bound receptor sites. Specifically, the RAR agonists are administered or coadministered with retinoid drugs to prevent or ameliorate toxicity or side effects caused by retinoids or vitamin A or vitamin A precursors. The retinoid negative hormones can be used to potentiate the activities of other retinoids and nuclear receptor agonists. For example, the retinoid negative hormone called AGN 193109 effectively increased the effectiveness of other retinoids and steroid hormones in in vitro transactivation assays. Additionally, transactivation assays can be used to identify compounds having negative hormone activity. These assays are based on the ability of negative hormones to down-regulate the activity of chimeric retinoid receptors engineered to possess a constitutive transcription activator domain.

摘要翻译： 芳基取代的和芳基和（3-氧代-1-丙烯基）取代的苯并吡喃，苯并噻喃，1,2-二氢喹啉和5,6-二氢萘衍生物具有类视黄醇阴性激素和/或拮抗剂样生物活性。 本发明的RAR拮抗剂可以施用于包括人在内的哺乳动物，以预防或减少RAR激动剂在结合受体位点上的作用。 具体来说，RAR激动剂与类视黄醇药物一起施用或共同施用以预防或改善由类维生素A或维生素A或维生素A前体引起的毒性或副作用。 类视黄醇阴性激素可用于增强其他类维生素A和核受体激动剂的活性。 例如，称为AGN 193109的类视黄醇阴性激素有效地增加了体外反式激活测定中其他类维生素A和类固醇激素的有效性。 另外，反式激活测定可用于鉴定具有负激素活性的化合物。 这些测定是基于负激素下调修饰的具有组成型转录激活子结构域的嵌合维甲酸受体的活性的能力。

公开(公告)号：US6034110A

公开(公告)日：2000-03-07

申请号：US5790

申请日：1998-01-12

申请人： Sunil Nagpal ,  Roshantha A. Chandraratna

发明人： Sunil Nagpal ,  Roshantha A. Chandraratna

IPC分类号： A61K45/06 ,  A61K31/44 ,  A61K31/19 ,  A61K31/38 ,  A61K31/415 ,  A61K31/425

CPC分类号： A61K45/06

摘要： A method is provided for preventing or reducing the risk of restenosis following angioplasty by administering a retinoid, such as an RXR-selective retinoid, e.g. the compound of the formula: ##STR1## and a PPAR.gamma. specific ligand and pharmaceutically acceptable salts and esters and amides thereof.

摘要翻译： 提供了一种通过施用类视黄醇（例如RXR-选择性类维生素A，例如紫杉醇）来预防或降低血管成形术后再狭窄的风险的方法。 下式的化合物：和PPARγ特异性配体及其药学上可接受的盐和酯和酰胺。