EA014941B1 - АГЕНТЫ ДЛЯ ПРЕДУПРЕЖДЕНИЯ И ЛЕЧЕНИЯ НАРУШЕНИЙ, ВКЛЮЧАЮЩИХ МОДУЛИРОВАНИЕ RyR РЕЦЕПТОРОВ - Google Patents
АГЕНТЫ ДЛЯ ПРЕДУПРЕЖДЕНИЯ И ЛЕЧЕНИЯ НАРУШЕНИЙ, ВКЛЮЧАЮЩИХ МОДУЛИРОВАНИЕ RyR РЕЦЕПТОРОВ Download PDFInfo
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- EA014941B1 EA014941B1 EA200800665A EA200800665A EA014941B1 EA 014941 B1 EA014941 B1 EA 014941B1 EA 200800665 A EA200800665 A EA 200800665A EA 200800665 A EA200800665 A EA 200800665A EA 014941 B1 EA014941 B1 EA 014941B1
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- Eurasian Patent Office
- Prior art keywords
- alkyl
- formula
- aryl
- disorders
- cycloalkyl
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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Landscapes
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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- Investigating Or Analysing Biological Materials (AREA)
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| PCT/US2006/032405 WO2007024717A2 (en) | 2005-08-25 | 2006-08-17 | Agents for preventing and treating disorders involving modulation of the ryr receptors |
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| US8022058B2 (en) * | 2000-05-10 | 2011-09-20 | The Trustees Of Columbia University In The City Of New York | Agents for preventing and treating disorders involving modulation of the RyR receptors |
| US7718644B2 (en) * | 2004-01-22 | 2010-05-18 | The Trustees Of Columbia University In The City Of New York | Anti-arrhythmic and heart failure drugs that target the leak in the ryanodine receptor (RyR2) and uses thereof |
| US7879840B2 (en) * | 2005-08-25 | 2011-02-01 | The Trustees Of Columbia University In The City Of New York | Agents for preventing and treating disorders involving modulation of the RyR receptors |
| US20060293266A1 (en) * | 2000-05-10 | 2006-12-28 | The Trustees Of Columbia | Phosphodiesterase 4D in the ryanodine receptor complex protects against heart failure |
| US20040229781A1 (en) * | 2000-05-10 | 2004-11-18 | Marks Andrew Robert | Compounds and methods for treating and preventing exercise-induced cardiac arrhythmias |
| US6489125B1 (en) * | 2000-05-10 | 2002-12-03 | The Trustees Of Columbia University In The City Of New York | Methods for identifying chemical compounds that inhibit dissociation of FKBP12.6 binding protein from type 2 ryanodine receptor |
| US20040048780A1 (en) * | 2000-05-10 | 2004-03-11 | The Trustees Of Columbia University In The City Of New York | Method for treating and preventing cardiac arrhythmia |
| US7393652B2 (en) * | 2000-05-10 | 2008-07-01 | The Trustees Of Columbia University In The City Of New York | Methods for identifying a chemical compound that directly enhances binding of FKBP12.6 to PKA-phosphorylated type 2 ryanodine receptor (RyR2) |
| US7544678B2 (en) * | 2002-11-05 | 2009-06-09 | The Trustees Of Columbia University In The City Of New York | Anti-arrythmic and heart failure drugs that target the leak in the ryanodine receptor (RyR2) |
| EP1603450A4 (en) * | 2003-03-07 | 2009-07-29 | Univ Columbia | PROCEDURE BASED ON TYPE 1 RYANODIN RECEPTOR |
| US8710045B2 (en) * | 2004-01-22 | 2014-04-29 | The Trustees Of Columbia University In The City Of New York | Agents for preventing and treating disorders involving modulation of the ryanodine receptors |
| US7704990B2 (en) | 2005-08-25 | 2010-04-27 | The Trustees Of Columbia University In The City Of New York | Agents for preventing and treating disorders involving modulation of the RyR receptors |
| WO2008144483A2 (en) * | 2007-05-18 | 2008-11-27 | Armgo Pharma, Inc. | Agents for treating disorders involving modulation of ryanodine receptors |
| KR101260859B1 (ko) | 2008-03-03 | 2013-05-06 | 르 라보레또레 쎄르비에르 | 감마-아미노알킬벤젠으로부터 벤조티아제핀을 제조하는 방법 |
| AU2008243144A1 (en) * | 2008-11-06 | 2010-05-20 | Quark Technologies Australia Pty Ltd | Improvements in Radiopharmaceutical Purification |
| CA2753345C (en) | 2009-02-25 | 2013-01-15 | Noboru Kaneko | 1,4-benzothiazepine-1-oxide derivative and pharmaceutical composition utilizing the same |
| US8933129B2 (en) | 2009-04-15 | 2015-01-13 | State Of Oregon By And Through The State Board Of Higher Education On Behalf Of Portland State University | Compounds and methods for modulating activity of calcium release channels |
| CN101812523B (zh) * | 2010-04-09 | 2012-08-22 | 广州益善生物技术有限公司 | Ryr1基因snp检测特异性引物、液相芯片和检测方法 |
| WO2012019076A1 (en) | 2010-08-06 | 2012-02-09 | The Trustees Of Columbia University In The City Of New York | Compositions and methods for preventing and treating cardiac ischemia/reperfusion injury |
| US9464322B2 (en) | 2011-09-09 | 2016-10-11 | University Of Kentucky Research Foundation | Methods for diagnosing and treating alzheimer's disease (AD) using the molecules that stabilize intracellular calcium (Ca2+) release |
| EP2708535A1 (en) | 2012-05-11 | 2014-03-19 | Les Laboratoires Servier | Agents for treating disorders involving modulation of ryanodine receptors |
| US9572528B1 (en) | 2012-08-06 | 2017-02-21 | Los Angeles Biomedical Research Insitute at Harbor-UCLA Medical Center | Monitor for SIDS research and prevention |
| WO2016168694A1 (en) * | 2015-04-15 | 2016-10-20 | Ohio State Innovation Foundation | Engineered calmodulin for treatment of ryanopathies |
| ES2643856B1 (es) | 2016-05-24 | 2018-08-03 | Universidad Del Pais Vasco / Euskal Herriko Unibertsitatea | Triazoles para la regulación de la homeostasis de calcio intracelular |
| US11758928B2 (en) | 2016-12-15 | 2023-09-19 | Société des Produits Nestlé S.A. | Compositions and methods that modulate phosphorus or enzymes in a companion animal |
| KR20240103036A (ko) * | 2017-07-06 | 2024-07-03 | 칠드런'즈 메디컬 센터 코포레이션 | 카테콜아민성 다형성 심실성 빈맥을 치료하거나 예방하기 위한 조성물 및 방법 |
| CN108588085B (zh) * | 2018-05-30 | 2021-11-09 | 上海市第十人民医院 | 恶性心律失常的筛查试剂盒、动物模型的建立方法及应用 |
| US11129871B1 (en) | 2018-06-19 | 2021-09-28 | Washington University | Compositions and methods for treating and preventing endoplasmic reticulum (ER) stress-mediated kidney diseases |
| EP4019089A4 (en) | 2019-07-22 | 2023-11-01 | Aetas Pharma Co. Ltd. | METHOD FOR PRODUCING AN OPTICALLY ACTIVE 1,4-BENZOTHIAZEPINE-1-OXIDE DERIVATIVE |
| BR112023009303A2 (pt) * | 2020-11-17 | 2024-02-06 | Armgo Pharma Inc | Agentes para tratar distúrbios envolvendo receptores de rianodina |
| KR20230129267A (ko) | 2021-01-08 | 2023-09-07 | 암고 파마, 인크. | 리아노딘 수용체 조정제의 결정질 형태 및 그의 용도 |
| WO2022246114A2 (en) | 2021-05-20 | 2022-11-24 | Armgo Pharma, Inc. | Pharmaceutical compositions comprising a ryanodine receptor modulator and uses thereof |
| EP4548971A1 (en) * | 2023-11-06 | 2025-05-07 | Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts, Universitätsmedizin | 1,4-benzothiazepines and related compounds with cyclopropanol groups as multi-targeted drugs |
| CN119632990B (zh) * | 2024-12-13 | 2025-11-18 | 温州医科大学 | 腔肠素在制备治疗心脏有关疾病的药物中的应用 |
| CN119977904A (zh) * | 2025-02-18 | 2025-05-13 | 合肥工业大学 | 一种苯并氧(碳/硫)氮杂䓬类化合物及其在医学上的应用 |
| CN121064313B (zh) * | 2025-11-07 | 2026-03-17 | 杭州宏望医学检验实验室有限公司 | 一种基于细胞法检测重症肌无力ryr1抗体的抗原及其应用 |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3519647A (en) * | 1966-10-12 | 1970-07-07 | Squibb & Sons Inc | 2,3,4,5-tetrahydro-1,5-benzothiazepines |
| US4963671A (en) * | 1989-11-20 | 1990-10-16 | E. R. Squibb & Sons, Inc. | Process for resolving chiral intermediates used in making calcium channel blockers |
| US5221681A (en) * | 1991-01-25 | 1993-06-22 | Bayer Aktiengesellschaft | Substituted benzoxazepines and benzothiazepines |
| US5580866A (en) * | 1992-11-09 | 1996-12-03 | The Boots Company Plc | Therapeutic 1,4-thiazepines |
| US6489125B1 (en) * | 2000-05-10 | 2002-12-03 | The Trustees Of Columbia University In The City Of New York | Methods for identifying chemical compounds that inhibit dissociation of FKBP12.6 binding protein from type 2 ryanodine receptor |
Family Cites Families (199)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1060786A (en) | 1963-10-09 | 1967-03-08 | Wander Ag Dr A | Process for the preparation of lactams |
| DE3561317D1 (en) | 1984-01-27 | 1988-02-11 | Ajinomoto Kk | Manufacture of heptanoic acid derivatives |
| US4567254A (en) | 1984-09-19 | 1986-01-28 | Kikkoman Corporation | Method for preparing N6,8-disubstituted 3',5'-cyclic adenosine monophosphate and salt thereof |
| JPS6260A (ja) | 1985-02-26 | 1987-01-06 | Ajinomoto Co Inc | シクロペンテニルヘプタン酸誘導体の製造方法 |
| US4723012A (en) | 1985-03-25 | 1988-02-02 | Japan Tobacco Inc. | Desmosine derivatives having a disulfide bond and preparation of artificial antigen using the same |
| US4841055A (en) | 1985-03-25 | 1989-06-20 | Japan Tobacco Inc. | Desmosine derivatives and reagent for preparing artificial antigens |
| DE3677201D1 (de) | 1986-03-27 | 1991-02-28 | Topy Ind | Oxidationskatalysator fuer kohlenmonoxyd. |
| US6956032B1 (en) | 1986-04-18 | 2005-10-18 | Carnegie Mellon University | Cyanine dyes as labeling reagents for detection of biological and other materials by luminescence methods |
| JPS63227599A (ja) | 1987-03-14 | 1988-09-21 | Kirin Brewery Co Ltd | アンスラサイクリン化合物およびその用途 |
| US5179125A (en) | 1987-12-03 | 1993-01-12 | Dainippon Pharmaceutical Co., Ltd. | N-substituted mercaptopropanamide derivatives |
| US5210266A (en) | 1987-12-03 | 1993-05-11 | Dainippon Pharmaceutical Co., Ltd. | N-substituted mercaptopropanamide derivatives |
| DE58901634D1 (de) | 1988-11-05 | 1992-07-16 | Bayer Ag | Verfahren zur kernchlorierung von aromatischen kohlenwasserstoffen. |
| US5272164A (en) | 1988-12-27 | 1993-12-21 | Kirin Beer Kabushiki Kaisha | Carboximidamide derivatives |
| US5223508A (en) | 1988-12-27 | 1993-06-29 | Kirin Beer Kabushiki Kaisha | Pyridyl carboximidamide compounds useful in treating blood pressure |
| JPH0662567B2 (ja) | 1988-12-27 | 1994-08-17 | 麒麟麦酒株式会社 | ピリジンカルボキシイミダミド誘導体、その製造中間体、製造法および用途 |
| US5142647A (en) | 1989-04-18 | 1992-08-25 | Japan Tobacco, Inc. | Magnus measuring apparatus |
| CA1341094C (en) * | 1989-09-25 | 2000-09-05 | Ronald G. Worton | Diagnosis for malignant hyperthermia |
| EP0446374B1 (en) | 1989-09-30 | 1996-02-07 | Kirin Beer Kabushiki Kaisha | Method of producing seedling |
| US5153184A (en) | 1989-10-10 | 1992-10-06 | Dowelanco | ((N-heterocyclyl)carbonyl)phosphoramidothioate ester insecticides |
| US5075293A (en) | 1989-10-10 | 1991-12-24 | The Dow Chemical Company | ((N-heterocyclyl)carbonyl)phosphoramidothioate ester insecticides |
| KR940000166B1 (ko) | 1989-11-09 | 1994-01-08 | 니혼다바고 상교오 가부시기가이샤 | 신규 글루코사민 유도체 및 이것을 막 구성성분으로서 함유한 리포솜 |
| KR940003297B1 (ko) | 1989-12-27 | 1994-04-20 | 니혼다바고 상교오 가부시기가이샤 | 1,3,2-디옥사티오렌옥시드 유도체 |
| US5204462A (en) | 1990-03-30 | 1993-04-20 | Japan Tobacco, Inc. | 4h-3,1-benzoxazin-4-one derivative |
| KR930700494A (ko) | 1990-04-10 | 1993-03-15 | 시게루 미즈노 | 신규한 옥사디논 유도체 |
| JP2651043B2 (ja) | 1990-07-10 | 1997-09-10 | 麒麟麦酒株式会社 | ジフェニルメチルピペラジン誘導体 |
| US5082847A (en) | 1990-07-18 | 1992-01-21 | Syntex (U.S.A.) Inc. | Carbostyril compounds connected via an oxyalkyl group with a piperidine ring and having pharmaceutical utility |
| US5064810A (en) | 1990-09-14 | 1991-11-12 | Jeffrey Askanazi | Use of branched chain amino acids to effect diaphragm contractility and fatigue |
| JP2703408B2 (ja) | 1990-12-28 | 1998-01-26 | 麒麟麦酒株式会社 | 1,4‐ベンゾチアゼピン誘導体 |
| US5180720A (en) | 1991-05-03 | 1993-01-19 | G. D. Searle & Co. | 2- and 3-alkoxy or hydroxy-8-substituted-dibenz[b,f]-[1,4]oxazepine-10(11H)-carboxylic acid, substituted hydrazides and methods for treating pain |
| US5182272A (en) | 1991-05-03 | 1993-01-26 | G. D. Searle & Co. | 8-substituted-dibenz[b,f][1,4]oxazepine-10(11)-carboxylic acid, substituted hydrazides, pharmaceutical compositions, and methods for treating pain |
| CA2090677C (en) | 1991-07-04 | 1996-08-27 | Yoshihiro Watanabe | Method for culturing t lineage precursor cells |
| EP0638560A4 (en) | 1991-10-11 | 1995-03-29 | Yoshitomi Pharmaceutical | MEDICINE FOR OSTEOPOROSIS AND DIAZEPINE COMPOUND *. |
| WO1993013082A1 (en) | 1991-12-20 | 1993-07-08 | G.D. Searle & Co. | Substituted dibenzoxazepines or dibenzothiazepines and their use as prostaglandin e2 antagonists |
| MX9300433A (es) | 1992-01-28 | 1994-07-29 | Kirin Brewery | Compuestos de piridincarboximidamina y composiciones farmaceuticas que los contienen. |
| GB9203347D0 (en) | 1992-02-17 | 1992-04-01 | Wellcome Found | Hypolipidaemic compounds |
| JP2667351B2 (ja) | 1992-03-24 | 1997-10-27 | 麒麟麦酒株式会社 | 食餌脂質消化吸収阻害剤および飲食品 |
| US5387684A (en) | 1992-03-25 | 1995-02-07 | The Green Cross Corporation | Isoindazole compound |
| JP3093419B2 (ja) | 1992-03-30 | 2000-10-03 | 麒麟麦酒株式会社 | 1,4‐ベンゾチアゼピン誘導体 |
| US5304644A (en) | 1992-04-15 | 1994-04-19 | G. D. Searle & Co. | 1-,2-,3-,4-,5-,6-,7-,8- and/or 9 substituted dibenzoxazepine compounds, pharmaceutical compositions and methods for treating pain |
| US5478832A (en) | 1992-05-08 | 1995-12-26 | The Green Cross Corporation | Quinoline compounds |
| RU94046317A (ru) | 1992-07-02 | 1996-10-20 | Фудзисава Фармасьютикал Ко. | Новое синтетическое промежуточное соединение для получения производных и способы получения производных аминокислот |
| CA2142883A1 (en) | 1992-08-21 | 1994-03-03 | Saizo Shibata | Dioxacycloalkane compound having renin-inhibitory activity |
| US5260286A (en) | 1992-10-16 | 1993-11-09 | Japan Tobacco, Inc. | 2-piperidinecarboxylic acid derivatives useful as NMDA receptor antagonists |
| US5354758A (en) | 1992-12-16 | 1994-10-11 | Japan Tobacco Inc. | Benzomorphans useful as NMDA receptor antagonists |
| ZA94284B (en) * | 1993-01-27 | 1994-08-17 | Shionogi & Co | Process for preparing benzothiazepine derivatives |
| IL108634A0 (en) | 1993-02-15 | 1994-05-30 | Wellcome Found | Hypolipidaemic heterocyclic compounds, their prepatation and pharmaceutical compositions containing them |
| IL108633A (en) | 1993-02-15 | 1998-07-15 | Wellcome Found | History of Benzothiazepine Hypolipidemic Preparation and Pharmaceutical Preparations Containing Them |
| EP0694558B1 (en) | 1993-04-15 | 1999-01-27 | Kirin Beer Kabushiki Kaisha | Novel sphingoglycolipid and use thereof |
| US5461047A (en) | 1993-06-16 | 1995-10-24 | G. D. Searle & Co. | 2-,3-,4-,5-,6-,7-,8-,9- and/or 10-substituted dibenzoxazepine and dibenzthiazepine compounds, pharmaceutical compositions and methods of use |
| US5354747A (en) | 1993-06-16 | 1994-10-11 | G. D. Searle & Co. | 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- and/or 10-substituted dibenzoxazepine and dibenzthiazepine compounds, pharmaceutical compositions and methods of use |
| US5824862A (en) | 1993-08-19 | 1998-10-20 | Japan Tobacco Inc. | DNA encoding ATP-dependent fructose 6-phosphate 1-phosphotransferase originating from plant, recombinant vector containing the same and method for changing sugar content in plant cells under low temperature |
| FR2709753B1 (fr) | 1993-09-09 | 1995-12-01 | Hoechst Lab | Nitrates organiques, leur procédé de préparation et leur application comme médicaments. |
| CA2153498A1 (en) | 1993-11-10 | 1995-05-18 | Hidetsura Cho | Chroman derivative and medicinal use thereof |
| US6897295B1 (en) | 1993-11-10 | 2005-05-24 | Mochida Pharmaceutical Co., Ltd. | Antibodies and fragments thereof to Fas ligand and Fas ligand derived polypeptides |
| JPH08127594A (ja) | 1993-11-10 | 1996-05-21 | Mochida Pharmaceut Co Ltd | Fas抗原に結合する新規蛋白質およびそれをコードするDNA |
| JP3914272B2 (ja) | 1993-12-28 | 2007-05-16 | 中外製薬株式会社 | アドゼベリンをコードする遺伝子 |
| JP2706755B2 (ja) | 1994-02-10 | 1998-01-28 | 日本たばこ産業株式会社 | 新規なベンジルアミノエトキシベンゼン誘導体 |
| US5457182A (en) | 1994-02-15 | 1995-10-10 | Merck & Co., Inc. | FK-506 cytosolic binding protein, FKBP12.6 |
| US5449675A (en) | 1994-06-09 | 1995-09-12 | G. D. Searle & Co. | Substituted dibenzoxazepine and dibenzthiazepine urea compounds, pharmaceutical compositions and methods of use |
| US20040175814A1 (en) | 1994-06-15 | 2004-09-09 | Kirin Beer Kubushiki Kaisha | Novel transferase and amylase, process for producing the enzymes, use thereof, and gene coding for the same |
| DE69534685T2 (de) | 1994-06-15 | 2006-09-07 | Kirin Beer K.K. | Transferase und amylase, verfahren zur herstellung dieser enzyme, ihre verwendung und für die kodierende gene |
| ZA956647B (en) | 1994-08-10 | 1997-02-10 | Wellcome Found | Hypolipidaemic compounds. |
| EP0741144B1 (en) | 1994-11-11 | 2002-07-24 | Noboru Kaneko | Antiannexin-v monoclonal antibody, process for producing the same, and use therof |
| CA2205173A1 (en) | 1994-11-18 | 1996-05-30 | Takeshi Nakamura | Therapeutic agent for osteoporosis and triazepine compound |
| US6632976B1 (en) | 1995-08-29 | 2003-10-14 | Kirin Beer Kabushiki Kaisha | Chimeric mice that are produced by microcell mediated chromosome transfer and that retain a human antibody gene |
| JP3193301B2 (ja) | 1995-09-14 | 2001-07-30 | 麒麟麦酒株式会社 | 生理活性タンパク質p160 |
| US6660837B1 (en) | 1995-09-14 | 2003-12-09 | Kirin Beer Kabushiki Kaisha | Modified protein derived from protein kinase N |
| US5906819A (en) | 1995-11-20 | 1999-05-25 | Kirin Beer Kabushiki Kaisha | Rho target protein Rho-kinase |
| US5866341A (en) | 1996-04-03 | 1999-02-02 | Chugai Pharmaceutical Co., Ltd. | Compositions and methods for screening drug libraries |
| US6362231B1 (en) | 1996-07-08 | 2002-03-26 | Nps Pharmaceuticals, Inc. | Calcium receptor active compounds |
| JP3861187B2 (ja) * | 1996-08-02 | 2006-12-20 | 住友精化株式会社 | チアゼピン誘導体の製造方法 |
| US6111072A (en) | 1996-08-26 | 2000-08-29 | Kirin Beer Kabushiki Kaisha | Rho target protein human mDia and gene encoding same |
| WO1998026053A1 (fr) | 1996-12-12 | 1998-06-18 | Kirin Beer Kabushiki Kaisha | NOUVELLE β1→4 N-ACETYLGLUCOSAMINYLTRANSFERASE ET GENE LA CODANT |
| TW555562B (en) | 1996-12-27 | 2003-10-01 | Kirin Brewery | Method for activation of human antigen-presenting cells, activated human antigen-presenting cells and use thereof |
| JP2894445B2 (ja) | 1997-02-12 | 1999-05-24 | 日本たばこ産業株式会社 | Cetp活性阻害剤として有効な化合物 |
| JP3521382B2 (ja) | 1997-02-27 | 2004-04-19 | 日本たばこ産業株式会社 | 細胞間接着及びシグナル伝達を媒介する細胞表面分子 |
| US7112655B1 (en) | 1997-02-27 | 2006-09-26 | Japan Tobacco, Inc. | JTT-1 protein and methods of inhibiting lymphocyte activation |
| JP3885177B2 (ja) | 1997-03-26 | 2007-02-21 | 大塚製薬株式会社 | ヒト遺伝子 |
| US6011036A (en) | 1997-04-15 | 2000-01-04 | Dr. Reddy's Research Foundation | Heterocyclic compounds having antidiabetic hypolipidemic antihypertensive properties process for their preparation and pharmaceutical compositions containing them |
| DE19722317C1 (de) | 1997-05-28 | 1998-10-08 | Boehringer Ingelheim Int | Das Protein des humanen Ryanodinrezeptors vom Typ 3 sowie dafür kodierende DNA-Moleküle |
| AUPO941497A0 (en) | 1997-09-24 | 1997-10-16 | Fujisawa Pharmaceutical Co., Ltd. | Novel compounds |
| CA2274776C (en) | 1997-10-08 | 2008-11-25 | Noboru Kaneko | Method for analyzing annexin v in urine and use thereof |
| GB9724813D0 (en) | 1997-11-25 | 1998-01-21 | Univ Nottingham | Reducing muscle fatigue |
| JP2959765B2 (ja) | 1997-12-12 | 1999-10-06 | 日本たばこ産業株式会社 | 3−ピペリジル−4−オキソキナゾリン誘導体及びそれを含有してなる医薬組成物 |
| WO1999033878A1 (en) | 1997-12-25 | 1999-07-08 | Japan Tobacco Inc. | Monoclonal antibody against connective tissue growth factor and medicinal uses thereof |
| US6583157B2 (en) | 1998-01-29 | 2003-06-24 | Tularik Inc. | Quinolinyl and benzothiazolyl modulators |
| US6051714A (en) | 1998-03-12 | 2000-04-18 | Reilly Industries, Inc. | Processes for dechlorinating pyridines |
| EP1072263A4 (en) | 1998-03-26 | 2004-03-31 | Japan Tobacco Inc | AMID DERIVATIVES AND NOCICEPTINANT AGONISTS |
| PL343424A1 (en) | 1998-04-10 | 2001-08-13 | Japan Tobacco Inc | Amidine compounds |
| CA2319142A1 (en) | 1998-06-08 | 1999-12-16 | Advanced Medicine, Inc. | Novel therapeutic agents for membrane transporters |
| US6890531B1 (en) | 1998-07-31 | 2005-05-10 | Kirin Beer Kabushiki Kaisha | Neuronal growth factor galectin-1 |
| EP1120119A4 (en) | 1998-09-17 | 2003-10-01 | Nippon Kayaku Kk | MEDICINE FOR PHOTOCHEMOTHERAPY |
| ATE314852T1 (de) | 1998-12-28 | 2006-02-15 | Noboru Kaneko | Verwendung von 1,4-benzothiazepinen zur herstellung eines medikaments zur behandlung der vorhof-fibrillation |
| DK1167537T3 (da) | 1999-03-30 | 2008-11-10 | Japan Tobacco Inc | Fremgangsmåde til fremstilling af et monoklonalt antistof |
| CA2373484C (en) | 1999-05-19 | 2009-01-20 | Noboru Kaneko | Use of 1,4-benzothiazepine derivatives as drugs for overcoming resistance to anticancer drugs |
| GB9914745D0 (en) * | 1999-06-24 | 1999-08-25 | Knoll Ag | Therapeutic agents |
| JP3871503B2 (ja) | 1999-08-30 | 2007-01-24 | 日本たばこ産業株式会社 | 免疫性疾患治療剤 |
| AU7097400A (en) | 1999-09-01 | 2001-03-26 | Otsuka Pharmaceutical Co., Ltd. | Platelet membrane glycoprotein vi (gpvi) dna and protein sequences, and uses thereof |
| DE60032620T2 (de) | 1999-09-30 | 2007-10-04 | Kaneko, Noboru | Antikrebsmittel |
| EP1243582A4 (en) | 1999-12-24 | 2003-06-04 | Kirin Brewery | CHINOLINE AND CHINAZOLINE DERIVATIVES AND MEDICATIONS CONTAINING THEM |
| DE60015392D1 (de) | 1999-12-29 | 2004-12-02 | Glaxo Group Ltd | Verwendung von annexin-modulatoren zur herstellung eines medikaments zur behandlung und/oder vorbeugung von arthritis und arthritischen erkrankungen |
| EP1247093B1 (en) | 2000-01-14 | 2005-03-23 | MIGENIX Corp. | Screening assays using intramitochondrial calcium |
| NZ519981A (en) | 2000-01-20 | 2005-02-25 | Eisai Co Ltd | Nitrogenous cyclic compounds and pharmaceutical compositions containing the same |
| US6809092B2 (en) * | 2000-01-26 | 2004-10-26 | Ono Pharmaceutical Co., Ltd. | Benezene-fused heteroring derivatives and pharmaceutical agents comprising the same as active ingredient |
| US6824973B2 (en) | 2000-02-03 | 2004-11-30 | Kirin Beer Kabushiki Kaisha | Method of promoting stem cell proliferation or survival by contacting a cell with a stem cell factor-like polypeptide |
| ATE420878T1 (de) | 2000-02-18 | 2009-01-15 | Kyowa Hakko Kirin Co Ltd | Isoxazol- und thiazolverbindungen und ihre verwendung als medikamente |
| DK1265859T3 (da) | 2000-03-24 | 2006-05-01 | Pharmacia Corp | Amidinoforbindelser der er nyttige som nitrogenoxidsyntaseinhibitorer |
| US6545170B2 (en) | 2000-04-13 | 2003-04-08 | Pharmacia Corporation | 2-amino-5, 6 heptenoic acid derivatives useful as nitric oxide synthase inhibitors |
| AR032318A1 (es) | 2000-04-13 | 2003-11-05 | Pharmacia Corp | Compuesto derivado halogenado del acido 2-amino-5,6 heptenoico; composicion farmaceutica que lo comprende y su uso en la fabricacion de un medicamento util como inhibidor de la oxido nitrico sintetasa |
| US6787668B2 (en) | 2000-04-13 | 2004-09-07 | Pharmacia Corporation | 2-amino-4,5 heptenoic acid derivatives useful as nitric oxide synthase inhibitors |
| AR034120A1 (es) | 2000-04-13 | 2004-02-04 | Pharmacia Corp | Compuesto derivado halogenado del acido 2-amino-4,5 heptenoico, composicion farmaceutica que lo comprende y el uso de dicho compuesto y dicha composicion en la fabricacion de un medicamento para inhibir o modular la sintesis de acido nitrico |
| US7879840B2 (en) | 2005-08-25 | 2011-02-01 | The Trustees Of Columbia University In The City Of New York | Agents for preventing and treating disorders involving modulation of the RyR receptors |
| US20040048780A1 (en) * | 2000-05-10 | 2004-03-11 | The Trustees Of Columbia University In The City Of New York | Method for treating and preventing cardiac arrhythmia |
| US20040229781A1 (en) | 2000-05-10 | 2004-11-18 | Marks Andrew Robert | Compounds and methods for treating and preventing exercise-induced cardiac arrhythmias |
| US20060293266A1 (en) | 2000-05-10 | 2006-12-28 | The Trustees Of Columbia | Phosphodiesterase 4D in the ryanodine receptor complex protects against heart failure |
| US7393652B2 (en) | 2000-05-10 | 2008-07-01 | The Trustees Of Columbia University In The City Of New York | Methods for identifying a chemical compound that directly enhances binding of FKBP12.6 to PKA-phosphorylated type 2 ryanodine receptor (RyR2) |
| US7718644B2 (en) | 2004-01-22 | 2010-05-18 | The Trustees Of Columbia University In The City Of New York | Anti-arrhythmic and heart failure drugs that target the leak in the ryanodine receptor (RyR2) and uses thereof |
| US8022058B2 (en) | 2000-05-10 | 2011-09-20 | The Trustees Of Columbia University In The City Of New York | Agents for preventing and treating disorders involving modulation of the RyR receptors |
| US20020132001A1 (en) | 2000-05-11 | 2002-09-19 | Garthwaite Susan M. | Aldosterone antagonist composition for release during aldosterone acrophase |
| US20030220312A1 (en) | 2000-05-11 | 2003-11-27 | G.D. Searle & Co. | Epoxy-steroidal aldosterone antagonist and calcium channel blocker combination therapy for treatment of cardiovascular disorders |
| CN101498731A (zh) | 2000-05-18 | 2009-08-05 | 日本烟草产业株式会社 | 抗协同刺激信号转导分子ailim的人单克隆抗体及其药物用途 |
| JP3597140B2 (ja) | 2000-05-18 | 2004-12-02 | 日本たばこ産業株式会社 | 副刺激伝達分子ailimに対するヒトモノクローナル抗体及びその医薬用途 |
| AU2001267879A1 (en) | 2000-07-05 | 2002-01-14 | Ajinomoto Co., Inc. | Acylsulfonamide derivatives |
| AU2001267878A1 (en) | 2000-07-05 | 2002-01-14 | Ajinomoto Co. Inc. | Hypoglycemics |
| AU2001278045B2 (en) | 2000-07-27 | 2006-08-03 | Pharmacia Corporation | Epoxy-steroidal aldosterone antagonist and calcium channel blocker combination therapy for treatment of congestive heart failure |
| WO2002010139A1 (en) | 2000-08-01 | 2002-02-07 | Pharmacia Corporation | Hexahydro-7-1h-azepin-2-yl-haxanoic acid derivatives as inhibitors of inducible nitric oxide synthase |
| AR031129A1 (es) | 2000-09-15 | 2003-09-10 | Pharmacia Corp | Derivados de los acidos 2-amino-2-alquil-4-hexenoico y -hexinoico utiles como inhibidores de oxido nitrico sintetasa |
| AR031608A1 (es) | 2000-09-15 | 2003-09-24 | Pharmacia Corp | Derivados de los acidos 2-amino-2-alquil-3-hexenoico y -hexinoico utiles como inhibidores de oxido nitrico sintetasa |
| MY131964A (en) | 2000-09-15 | 2007-09-28 | Pharmacia Corp | 2-amino-2-alkyl-5 heptenoic and heptynoic acid derivatives useful as nitric oxide synthase inhibitors |
| US6936426B2 (en) | 2000-10-06 | 2005-08-30 | Harbor-Ucla Research And Education Institute | Detection of antibody mediated inflammatory auto-immune disorders |
| CN1487996B (zh) | 2000-11-30 | 2010-06-16 | 米德列斯公司 | 用于生产人类抗体的转基因转染色体啮齿动物 |
| US6673904B2 (en) | 2000-12-23 | 2004-01-06 | Kirin Beer Kabushiki Kaisha | Stem cell growth factor-like polypeptides |
| US6962926B2 (en) | 2001-01-31 | 2005-11-08 | Telik, Inc. | Antagonist of MCP-1 function, and compositions and methods of use thereof |
| JPWO2002061076A1 (ja) | 2001-02-01 | 2004-06-03 | 持田製薬株式会社 | アディポネクチン関連蛋白質 |
| JP4817514B2 (ja) | 2001-03-09 | 2011-11-16 | 協和発酵キリン株式会社 | 新規動物細胞用ベクターおよびその使用 |
| WO2002072145A1 (en) | 2001-03-14 | 2002-09-19 | Ono Pharmaceutical Co., Ltd. | Remedies for depression containing ep1 antagonist as the active ingredient |
| US20030054531A1 (en) | 2001-03-19 | 2003-03-20 | Decode Genetics Ehf, | Human stroke gene |
| WO2002078625A2 (en) | 2001-03-28 | 2002-10-10 | Pharmacia Corporation | Therapeutic combinations for cardiovascular and inflammatory indications |
| EP1652847B1 (en) | 2001-04-27 | 2008-05-28 | Kirin Pharma Kabushiki Kaisha | Quinoline and quinazoline derivatives for the treatment of tumors |
| JP4230681B2 (ja) | 2001-07-06 | 2009-02-25 | 株式会社東芝 | 高耐圧半導体装置 |
| US20030220310A1 (en) | 2001-07-27 | 2003-11-27 | Schuh Joseph R. | Epoxy-steroidal aldosterone antagonist and calcium channel blocker combination therapy for treatment of congestive heart failure |
| GB0121621D0 (en) * | 2001-09-07 | 2001-10-31 | Astrazeneca Ab | Chemical compounds |
| EP1435946B8 (en) | 2001-09-14 | 2013-12-18 | Amgen Inc. | Linked biaryl compounds |
| JP2003095977A (ja) * | 2001-09-21 | 2003-04-03 | Masafumi Yano | 筋肉収縮・弛緩機能障害関連疾患の治療又は予防剤 |
| US20050177884A1 (en) | 2001-11-15 | 2005-08-11 | Kirin Beer Kabushiki Kaisha | Chimeric nonhuman animal |
| JP2003145746A (ja) | 2001-11-16 | 2003-05-21 | Seiko Epson Corp | インクジェット記録方法及びインクジェット記録装置 |
| JPWO2003043655A1 (ja) | 2001-11-19 | 2005-03-10 | 小野薬品工業株式会社 | 頻尿の治療剤 |
| WO2003048140A1 (en) | 2001-12-03 | 2003-06-12 | Japan Tobacco Inc. | Azole compound and medicinal use thereof |
| WO2003061699A1 (en) | 2001-12-27 | 2003-07-31 | Japan Tobacco, Inc. | Remedies for allergic diseases |
| US20040171613A1 (en) | 2001-12-27 | 2004-09-02 | Japan Tobacco Inc. | Therapeutic agent for non-immediate type allergic diseases |
| BR0306643A (pt) | 2002-01-17 | 2004-10-19 | Pharmacia Corp | Novos compostos de hidroxi alquil/aril ou ceto tiepina como inibidores do transporte co-dependente de ácido biliar-sódio apical |
| TWI262917B (en) | 2002-02-01 | 2006-10-01 | Dainippon Sumitomo Pharma Co | 2-Furancarboxylic hydrazides and pharmaceutical compositions containing the same |
| KR100993113B1 (ko) | 2002-02-14 | 2010-11-08 | 기린 홀딩스 가부시키가이샤 | 지질대사 개선용 조성물 및 식품 |
| US7439332B2 (en) | 2002-04-26 | 2008-10-21 | Kirin Pharma Kabushiki Kaisha | Polypeptide having an activity to support proliferation or survival of hematopoietic stem or progenitor cells |
| CN1655696A (zh) | 2002-04-26 | 2005-08-17 | 日本烟草产业株式会社 | 棒状物品成形装置 |
| JP4113042B2 (ja) | 2002-05-24 | 2008-07-02 | シチズンホールディングス株式会社 | 表示装置およびカラー表示方法 |
| DE10237723A1 (de) | 2002-08-17 | 2004-07-08 | Aventis Pharma Deutschland Gmbh | Verwendung von IKappaB-Kinase Inhibitoren in der Schmerztherapie |
| BR0306208A (pt) | 2002-08-30 | 2004-10-13 | Japan Tobacco Inc | Compostos de dibenzilamina e seu uso farmacêutico |
| JP2004103256A (ja) | 2002-09-04 | 2004-04-02 | Nippon Chemicon Corp | 非常灯 |
| EP1550660A1 (en) | 2002-09-12 | 2005-07-06 | Kirin Beer Kabushiki Kaisha | Isoquinoline derivatives having kinasae inhibitory activity and drugs containing the same |
| WO2004026318A1 (ja) | 2002-09-20 | 2004-04-01 | Kirin Beer Kabushiki Kaisha | α-グリコシルセラミドを有効成分とするC型肝炎ウイルス抑制剤 |
| US20060185025A1 (en) | 2002-10-04 | 2006-08-17 | Kirin Beer Kabushiki Kaisha | Human artificial chromosome (hac) vector |
| US7544678B2 (en) | 2002-11-05 | 2009-06-09 | The Trustees Of Columbia University In The City Of New York | Anti-arrythmic and heart failure drugs that target the leak in the ryanodine receptor (RyR2) |
| AU2003301894A1 (en) | 2002-11-08 | 2004-06-07 | Bayer Healthcare Ag | Diagnostics and therapeutics for diseases associated with human phosphodiesterase 4d (pde4d) |
| KR100772297B1 (ko) | 2002-11-22 | 2007-11-02 | 니뽄 다바코 산교 가부시키가이샤 | 융합 비시클릭 질소-함유 헤테로사이클 |
| EP1439221B1 (en) | 2002-12-17 | 2007-01-24 | F. Hoffmann-La Roche Ag | PDE core construct |
| EP1598349B1 (en) | 2003-02-13 | 2011-07-27 | Msd K.K. | Novel 2-pyridinecarboxamide derivatives |
| TWI220798B (en) | 2003-03-07 | 2004-09-01 | Hitachi Cable | Light-emitting diode array |
| EP1603450A4 (en) | 2003-03-07 | 2009-07-29 | Univ Columbia | PROCEDURE BASED ON TYPE 1 RYANODIN RECEPTOR |
| MXPA05009848A (es) | 2003-03-17 | 2005-12-06 | Japan Tobacco Inc | Composiciones farmaceuticas de inhibidores de la proteina de transferencia del ester de colesterilo. |
| WO2004082675A1 (en) | 2003-03-17 | 2004-09-30 | Japan Tobacco Inc. | Method for increasing the oral bioavailability of s-[2- ([[1- (2-ethylbutyl) cyclohexyl] carbonyl] amino) phenyl] 2-methylpropanethioate |
| US20050032210A1 (en) | 2003-03-18 | 2005-02-10 | Kirin Beer Kabushiki Kaisha | Method of preparing immuno-regulatory dendritic cells and the use thereof |
| US20040235162A1 (en) | 2003-03-18 | 2004-11-25 | Kirin Beer Kabushiki Kaisha | Method of preparing immunoregulatory dendritic cells and the use thereof |
| CL2004000544A1 (es) | 2003-03-18 | 2005-01-28 | Pharmacia Corp Sa Organizada B | Uso de una combinacion farmaceutica, de un antagonista del receptor de aldosterona y un inhibidor de endopeptidasa neutral, util para el tratamiento y prevencion de una condicion patologica relacionada con hipertension, disfuncion renal, insulinopati |
| WO2004085382A1 (ja) | 2003-03-27 | 2004-10-07 | Kirin Beer Kabushiki Kaisha | 生体内リン輸送を阻害する化合物およびそれを含んでなる医薬 |
| MXPA05010945A (es) | 2003-04-09 | 2005-11-25 | Japan Tobacco Inc | Compuesto pentaciclico heteroaromatico y uso medicinal del mismo. |
| US20040229803A1 (en) | 2003-04-22 | 2004-11-18 | Pharmacia Corporation | Compositions of a cyclooxygenase-2 selective inhibitor and a potassium ion channel modulator for the treatment of pain, inflammation or inflammation mediated disorders |
| WO2004093816A2 (en) | 2003-04-22 | 2004-11-04 | Pharmacia Corporation | Compositions comprising a selective cox-2 inhibitor and a calcium modulating agent |
| US20060135506A1 (en) | 2003-04-22 | 2006-06-22 | Pharmacia Corporation | Compositions of a cyclooxygenase-2 selective inhibitor and a calcium modulating agent for the treatment of pain, inflammation or inflammation mediated disorders |
| US20050009733A1 (en) | 2003-04-22 | 2005-01-13 | Pharmacia Corporation | Compositions of a cyclooxygenase-2 selective inhibitor and a potassium ion channel modulator for the treatment of central nervous system damage |
| TWI494102B (zh) | 2003-05-02 | 2015-08-01 | Japan Tobacco Inc | 包含s-〔2(〔〔1-(2-乙基丁基)環己基〕羰基〕胺基)苯基〕2-甲基丙烷硫酯及hmg輔酶a還原酶抑制劑之組合 |
| WO2005016249A2 (en) | 2003-07-11 | 2005-02-24 | Pharmacia Corporation | Compositions of a chromene or phenyl acetic acid cyclooxygenase-2 selective inhibitor and an ace inhibitor for the treatment of central nervous system damage |
| EP1653969A4 (en) | 2003-08-07 | 2006-12-20 | Japan Tobacco Inc | PYRROLO 1,2-B PYRIDAZINE DERIVATIVES |
| JP2007502831A (ja) | 2003-08-20 | 2007-02-15 | ニトロメッド インコーポレーティッド | ニトロソ化およびニトロシル化心血管化合物、組成物、ならびに使用方法 |
| CA2536975A1 (en) | 2003-08-28 | 2005-03-17 | Nitromed, Inc. | Nitrosated and nitrosylated diuretic compounds, compositions and methods of use |
| US20050187221A1 (en) | 2003-09-08 | 2005-08-25 | Japan Tobacco Inc. | Method of treating ischemia reperfusion injury |
| JP2007515490A (ja) | 2003-12-22 | 2007-06-14 | アムジェン インコーポレーティッド | アリールスルホンアミド化合物およびそれに関連する使用法 |
| US7165879B2 (en) | 2004-03-25 | 2007-01-23 | Red Devil Equipment Company | Clamp lock apparatus and method for a paint mixer |
| NZ550106A (en) | 2004-04-22 | 2009-06-26 | Kyowa Hakko Kirin Co Ltd | Transgenic animals and uses thereof |
| CA2565024A1 (en) | 2004-04-28 | 2005-11-10 | Aetas Pharma Co., Ltd. | Therapeutic agent for left ventricular diastolic dysfunction |
| US7378423B2 (en) | 2004-06-11 | 2008-05-27 | Japan Tobacco Inc. | Pyrimidine compound and medical use thereof |
| JP3968358B2 (ja) | 2004-06-30 | 2007-08-29 | 日本電信電話株式会社 | 薄型フラットツイストぺアすきまケーブル及びすきまナビゲータユニット |
| KR101042490B1 (ko) | 2004-07-15 | 2011-06-16 | 니뽄 다바코 산교 가부시키가이샤 | 축합 벤즈아미드 화합물 및 바닐로이드 수용체 1형(vr1)활성 저해제 |
| JP2006094849A (ja) | 2004-08-30 | 2006-04-13 | Kirin Brewery Co Ltd | 相同組換え効率が向上した分化多能性細胞及びその利用 |
| AR051780A1 (es) | 2004-11-29 | 2007-02-07 | Japan Tobacco Inc | Compuestos en anillo fusionados que contienen nitrogeno y utilizacion de los mismos |
| WO2006091716A2 (en) | 2005-02-24 | 2006-08-31 | Nitromed, Inc. | Nitric oxide enhancing diuretic compounds, compositions and methods of use |
| WO2006093247A1 (ja) | 2005-02-28 | 2006-09-08 | Japan Tobacco Inc. | Syk阻害活性を有する新規なアミノピリジン化合物 |
| WO2006098394A1 (ja) | 2005-03-14 | 2006-09-21 | Japan Tobacco Inc. | 脂質吸収抑制方法および脂質吸収抑制剤 |
| US7704990B2 (en) | 2005-08-25 | 2010-04-27 | The Trustees Of Columbia University In The City Of New York | Agents for preventing and treating disorders involving modulation of the RyR receptors |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3519647A (en) * | 1966-10-12 | 1970-07-07 | Squibb & Sons Inc | 2,3,4,5-tetrahydro-1,5-benzothiazepines |
| US4963671A (en) * | 1989-11-20 | 1990-10-16 | E. R. Squibb & Sons, Inc. | Process for resolving chiral intermediates used in making calcium channel blockers |
| US5221681A (en) * | 1991-01-25 | 1993-06-22 | Bayer Aktiengesellschaft | Substituted benzoxazepines and benzothiazepines |
| US5580866A (en) * | 1992-11-09 | 1996-12-03 | The Boots Company Plc | Therapeutic 1,4-thiazepines |
| US6489125B1 (en) * | 2000-05-10 | 2002-12-03 | The Trustees Of Columbia University In The City Of New York | Methods for identifying chemical compounds that inhibit dissociation of FKBP12.6 binding protein from type 2 ryanodine receptor |
Non-Patent Citations (5)
| Title |
|---|
| GAILLY. New aspects of calcium signaling in skeletal muscle cells: Implications in Duchenne muscular dystrophy. Blochimica et Biophysica Acta, Sep 2002, 1600(1-2):38-44, pg 39, LHS para 1; pg 38, Abstract & LHS para below * |
| LAFERLA. Calcium dyshomeostasis and intracellular signaling in Alzheimer's disease. Nature Reviews. Nov 2002, 3(11):862-872, pg 866, middle col, para 2; pg 862 RHS para 1 * |
| MacKENZIE et al.: The role of inositol 1,4,5-triphosphate receptors in Ca+2 signaling arid the generation of arrhythmias in rat atrial monocytes. J. Physiol Mar 2002, 541(2):395-409; pg 395, Abstract: pg 396 LHS para 2 * |
| TAUR et at.: The Cardiac Ryanodine Receptor (RyR2) and its Role in Heart Disease. Cardiology in Review June 2005, 13(3):142-6 * |
| YANO et al.: FKBP12.6-mediated stabilization of calcium-release channel (Ryanodine Receptor) as a novel therapeutic strategy against heart falture. Circulation, Journal of the American Heart Association Jan 2003,107(3):477-484; pg 477, Abstract; paras "Background", "Methods & Results" and "Conclusion" * |
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