A RANDOMIZED, DOUBLE BLIND, PLACEBO CONTROLLED STUDY TO EVALUATE THE SAFETY, TOLERABILITY AND PRELIMINARY EFFICACY OF A FOUR-WEEK TREATMENT WITH YM758 IN SUBJECTS WITH STABLE ANGINA. - IRIS

开始日期2006-04-21

申办/合作机构

Astellas Pharma Europe Ltd.

100 项与 YM-758 相关的临床结果

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100 项与 YM-758 相关的转化医学

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100 项与 YM-758 相关的专利（医药）

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项与 YM-758 相关的文献（医药）

2016-06-01·Drugs in R&D4区 · 医学

Investigation of Metabolite Profile of YM758, a Novel If Channel Inhibitor

4区 · 医学

ArticleOA

作者: Nakada, Naoyuki

BACKGROUNDYM758 monophosphate is a novel If channel inhibitor that has an inhibitory action for If current and shows a strong and specific activity, selectively lowering the heart rate and decreasing oxygen consumption by heart muscle.OBJECTIVESThe objectives of the current study were to investigate the in vivo metabolic profiles of YM758 in mice, rats, rabbits, dogs, and monkeys and to elucidate the structures of YM758 metabolites.METHODSBiological samples were analyzed by liquid chromatography hyphenated with a radiometric detection system and liquid chromatography coupled with a mass spectrometer to clarify their metabolic patterns. To elucidate their structures, metabolites were isolated and analyzed by mass spectrometry and nuclear magnetic resonance spectroscopy.RESULTSOur results from in vivo metabolic profiling in humans and animals indicated there is no significant species difference in the metabolism of YM758, and the metabolic pathways of YM758 are considered to be oxidation, hydration, and demethylation followed by sulfate or glucuronide conjugation.

2014-12-19·Organic Process Research & Development

Development of a Practical and Scalable Synthetic Route to YM758 Monophosphate, A Novel I_f Channel Inhibitor

作者: Takahashi, Takumi ; Mase, Toshiyasu ; Takeguchi, Kazuhiro ; Yoshida, Shinya ; Marumo, Kiyotaka

A novel, practical, and efficient synthesis of (-)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide monophosphate I·H₃PO₄ (YM758 monophosphate, (R)-1·H₃PO₄) is described.The target mol. (R)-1 is a potent I_f current channel inhibitor.The known synthetic routes were very long and suffered from extensive use of chlorinated solvents and silica-gel column chromatog.A number of steps in the existing route were also unattractive for large-scale synthesis due to some reasons for example the use of unstable intermediates.An important objective of a new synthetic route was avoidance of such a use of unstable intermediate, and it was achieved by the discovery of an important intermediate, 2-(4-fluorophenyl)-4,5-dihydrooxazole (19) and ring-opening N-alkylation of chiral amine with 19 under acidic condition.The new procedure does not require any purification by column chromatog. for all steps.The overall yield was significantly improved from 14% or 34% to 49% compared to that of the medicinal synthetic routes.This highly efficient process was successfully demonstrated at a pilot-scale operation, yielding 36.5 kg of (R)-1·H₃PO₄.

2009-11-01·Drug Metabolism and Disposition2区 · 医学

Investigation of Long-Term Retention of Unchanged (−)-N-{2-[(R)-3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide, A Novel “Funny” If Current Channel Inhibitor, and Its Metabolites in the Eyeball and Thoracic Aorta of Rats

2区 · 医学

Article

作者: Noguchi, Kiyoshi ; Umehara, Ken-ichi ; Usui, Takashi ; Iwatsubo, Takafumi ; Kamimura, Hidetaka ; Nakada, Naoyuki

(-)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a novel "funny" If current channel inhibitor, was being developed as a treatment for stable angina and atrial fibrillation. After a single oral administration of (14)C-YM758, extensive accumulation and long-term retention of radioactivity were observed in the eyeballs of nonalbino rats and in the thoracic aorta of albino/nonalbino rats. Radioluminograms of the eyeballs of nonalbino rats indicated that the radioactivity was localized to the uveal tract, which suggests that the radioactivity may be positively charged and bound mainly to the melanins. Treatment with a mixture of 2 mol/l hydrochloric acid and methanol (5:95, v/v) allowed for the recovery of the major portion of radioactivity from the eyeball, which suggests reversible binding. The radioactive constituents in eyeballs consisted of the unchanged drug (YM758) and three metabolites [mainly 6,7-dimethoxy-2-[(3R)-piperidin-3-ylcarbonyl]-1,2,3,4-tetrahydroisoquinoline (YM-252124)]. Using the organic solvent mixture described above, almost all of the radioactivity was not collected from the thoracic aorta, and approximately 90% was recovered by treatment with elastase, which suggests that some metabolites covalently bind to the elastin fiber localized in the tunica media.

100 项与 YM-758 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
稳定型心绞痛	临床2期	斯洛伐克	Astellas Pharma, Inc.	2006-04-21
心绞痛	临床2期	欧洲	Cardeus Pharmaceuticals, Inc.	-
心房颤动	临床2期	美国	Cardeus Pharmaceuticals, Inc.	-
心房颤动	临床2期	-	Astellas Pharma, Inc.	-