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

Start Date21 Apr 2006

Sponsor / Collaborator

Astellas Pharma Europe Ltd.

100 Clinical Results associated with YM-758

100 Translational Medicine associated with YM-758

100 Patents (Medical) associated with YM-758

Literatures (Medical) associated with YM-758

01 Jun 2016·Drugs in R&DQ4 · MEDICINE

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

Q4 · MEDICINE

ArticleOA

Author: 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.

19 Dec 2014·Organic Process Research & Development

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

Author: 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.

01 Nov 2009·Drug Metabolism and DispositionQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: 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 Deals associated with YM-758

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Indication	Highest Phase	Country/Location	Organization	Date
Angina, Stable	Phase 2	Slovakia	Astellas Pharma, Inc.	21 Apr 2006
Angina Pectoris	Phase 2	Europe	Cardeus Pharmaceuticals, Inc.	-
Atrial Fibrillation	Phase 2	United States	Cardeus Pharmaceuticals, Inc.	-
Atrial Fibrillation	Phase 2	-	Astellas Pharma, Inc.	-

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