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.

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.

01 Aug 2009·Drug Metabolism and DispositionQ2 · MEDICINE

Identification of Human Metabolites of (–)-N-{2-[(R)-3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a Novel If Channel Inhibitor, and Investigation of the Transporter-Mediated Renal and Hepatic Excretion of These Metabolites

Q2 · MEDICINE

Article

Author: Iwatsubo, Takafumi ; Shirai, Nobuaki ; Umehara, Ken-ichi ; Usui, Takashi ; Noguchi, Kiyoshi ; Kamimura, Hidetaka

(-)-N-{2-[(R)-3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758) is a novel inhibitor of the "funny" If current channel (If channel) that is expressed in the sinus node of heart and is being developed as a treatment for stable angina and atrial fibrillation. Its metabolites were identified in human urine, plasma, and feces by radio-high-performance liquid chromatography and liquid chromatography-tandem mass spectrometry analyses after oral administration of [(14)C]YM758. 6,7-Dimethoxy-2-[(3R)-piperidin-3-ylcarbonyl]-1,2,3,4-tetrahydroisoquinoline (YM-252124), (5R)-5-[(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]piperidin-2-one (YM-385459), 2-{[(3R)-1-{2-[(4-fluorobenzoyl)amino]ethyl}piperidin-3-yl]carbonyl}-7-methoxy-1,2,3,4-tetrahydroisonolin-6-yl beta-D-glucopyranosiduronic acid (AS2036329), and the unchanged drug were detected as major constituents in both urine and plasma, whereas N-(4-fluorobenzoyl)glycine (YM-385461) was detected in plasma, but not in urine. The renal and hepatic uptake transporters for these metabolites were investigated by assessing their inhibitory effect on uptake activity in human (h) organic cation transporter (OCT) 1-3/rat (r) Oct1-3, human organic anion transporter (OAT) 1/rOat1, hOAT3/rOat3, and organic anion-transporting protein 1B1/1B3-expressing HEK293 cells. IC(50) values of YM-252124 for 1-methyl-4-phenylpyridinium uptake via hOCT2 and rOct2 were 93.9 and 1700 microM, respectively, suggesting that this metabolite is secreted into urine via hOCT2/rOct2 and that the large difference in the inhibitory potentials between hOCT2 and rOct2 explains the species difference in the urinary excretion ratio of the radioactivity. The renal secretion of YM-385461, one derivative of p-aminohippuric acid, via hOAT1/rOat1, and hepatic uptake of YM-252124 via hOCT1/rOct1 was also expected. This kind of study was useful in investigating the relationship between the urinary/hepatic elimination and the transport activity for metabolites.

100 Deals associated with YM-758

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

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