Neuroprotective effects of an AMPA receptor antagonist YM872 in a rat transient middle cerebral artery occlusion model

Kawasaki-Yatsugi, Sachiko; Ichiki, Chikako; Yatsugi, Shin-ichi; Takahashi, M; Shimizu‐Sasamata, Masao; Yamaguchi, Tokio; Minematsu, Kazuo

doi:10.1016/s0028-3908(99)00117-3

Cited by 33 publications

(15 citation statements)

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“…For this study, eight aldehydes (1)(2)(3)(4)(5)(6)(7)(8) and eight sulfonamides (A-H) were used to conceptualize an 8 Â 8 grid, where each matrix element represents the benzothiadiazide produced from the reaction between a sulfonamide (A-H, the x-axis) and an aldehyde (1-8, the y-axis). Rather than preparing all members of the library individually (64 in all in this study) and assaying them individually, the indexed approach allows one to identify new 'active hits' through preparing and assaying compound pools.…”

Section: Background On the Indexed Library Approachmentioning

confidence: 99%

“…Then, the reaction was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with brine, and processed in the usual way to give the crude product. Flash chromatography (40% ethyl acetate/hexanes) gave the title compound (681 mg, 96%); mp 150-151 C. 1 2-(4-Benzyl-7-fluoro-3,5-dimethyl-1,1-dioxo-3,4-dihydro-1H-benzo [1,2,4]thiadiazin-2-yl)-ethanol (26f). Compound 26e (300 mg, 0.77 mmol) was dissolved in THF (5.0 mL) and cooled to 0 C. Lithium aluminumhydride (0.0404 g, 1.1 mmol) was dissolved in THF (6.0 mL) and cooled to 0 C in a separate flask.…”

Section: -mentioning

confidence: 99%

“…3 Major efforts are accordingly being made to develop receptor antagonists which afford protection during those critical periods. 3,4 Insufficient activation of glutamate receptors may be of similar clinical importance, but is more likely associated with chronic disorders. One example may be the progressive loss of synapses or neurons in age and agerelated disorders.…”

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5′-Alkyl-benzothiadiazides: A New Subgroup of AMPA Receptor Modulators with Improved Affinity

Phillips

Sonnenberg

Arai

et al. 2002

Bioorganic & Medicinal Chemistry

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Section: Background On the Indexed Library Approachmentioning

confidence: 99%

Section: -mentioning

confidence: 99%

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confidence: 99%

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5′-Alkyl-benzothiadiazides: A New Subgroup of AMPA Receptor Modulators with Improved Affinity

Phillips

Sonnenberg

Arai

et al. 2002

Bioorganic & Medicinal Chemistry

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“…One promising AMPA antagonist, YM872, has demonstrated reduced infarct volume comparable to NMDA receptor antagonists in animal models. 44 Enrollment has just been terminated prematurely in two concurrent YM872 clinical trials, the ARTIST (AMPA Receptor Antagonist Treatment in Ischemic Stroke) trials, based on an interim futility analysis. These multicenter, randomized, double-blind, placebo-controlled trials were designed to "fill in the gaps" left by past neuroprotection trials-combination of reperfusion and neuroprotection strategies, and use of a biologic marker of efficacy.…”

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confidence: 99%

Clinical trials for cytoprotection in stroke

Labiche

Grotta

2004

Neurotherapeutics

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Summary:To date, many cytoprotective drugs have reached the stage of pivotal phase 3 efficacy trials in acute stroke patients. (Table 1) Unfortunately, throughout the neuroprotective literature, the phrase "failure to demonstrate efficacy" prevails as a common thread among the many neutral or negative trials, despite the largely encouraging results encountered in preclinical studies. The reasons for this discrepancy are multiple, and have been discussed by Dr. Zivin in his review. Many of the recent trials have addressed deficiencies of the previous ones with more rigorous trial design, including more specific patient selection criteria (ensure homogeneity of stroke location and severity), stratified randomization algorithms (time-totreat), narrowed therapeutic time-window and pharmacokinetic monitoring. Current trials have also incorporated biologic surrogate markers of toxicity and outcome such as drug levels and neuroimaging. Lastly, multi-modal therapies and coupled cytoprotection/reperfusion strategies are being investigated to optimize tissue salvage. This review will focus on individual therapeutic strategies and we will emphasize what we have learned from these trials both in terms of trial design and the biologic effect (or lack thereof) of these agents.

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“…1) YM872 has been shown to provide neuroprotection in a variety of animal models of ischemia. [2][3][4] In this study, 14 C-labeled YM872 ( 14 C-YM872) was intravenously administered to rats in order to measure urinary excretion of radioactivity and metabolic fingerprinting in urine. Furthermore, two metabolites were semi-purified by preparative HPLC from rat urine after a single intravenous administration of non-labeled YM872, and their structures were elucidated by various instrumental analyses using high-resolution matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (HR-MALDI-TOFMS), LC-MS, LC-MS/MS, and LC-NMR.…”

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Application of LC-NMR for Characterization of Rat Urinary Metabolites of Zonampanel Monohydrate (YM872)

Sohda¹,

Minematsu²,

Hashimoto³

et al. 2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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Zonampanel monohydrate (YM872, Fig. 1) was discovered to be a novel competitive a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist, which is a highly water-soluble agent with the selectivity and potency for AMPA receptors. 1) YM872 has been shown to provide neuroprotection in a variety of animal models of ischemia. [2][3][4] In this study, 14 C-labeled YM872 ( 14 C-YM872) was intravenously administered to rats in order to measure urinary excretion of radioactivity and metabolic fingerprinting in urine. Furthermore, two metabolites were semi-purified by preparative HPLC from rat urine after a single intravenous administration of non-labeled YM872, and their structures were elucidated by various instrumental analyses using high-resolution matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (HR-MALDI-TOFMS), LC-MS, LC-MS/MS, and LC-NMR.LC-NMR has been recently used for metabolite structure determination.5-7) LC-NMR elucidates the structure of trace components in mixtures and unstable compounds which are easily decomposed during purification and evaporation to dryness. LC-NMR is more suitable for the two YM872 metabolites than conventional NMR because they are trace components in urine and one of them is likely to be unstable at room temperature. For these reasons, LC-NMR was selected as the method of choice. Results and DiscussionUrinary excretion of total radioactivity was 75.6Ϯ7.4% of dose [meanϮstandard deviation (SD) of 4 rats] from 0 to 8 h after a single intravenous administration of 14 C-YM872. On the HPLC radiochromatogram of the rat urine collected from 0 to 8 h after administration, a major peak corresponding to the parent compound was observed at about 26 min and small metabolite peaks were observed at about 17 and 19.5 min (Fig. 2). Urinary excretion of radioactivity for each peak at about 17 (R1), 19.5 (R2), and 26 min (the parent compound) were 0.7Ϯ0.2%, 0.8Ϯ0.5%, and 71.5Ϯ6.3% of dose (meanϮSD of 4 rats), respectively. In the fingerprinting study, storage temperature was shown to influence urinary metabolites (data not shown). HPLC radiochromatogram of the rat urine after storage for about 24 h at room temperature showed that the peak of R1 decreased, whereas the peak of R2 increased. In contrast, there was no change after storage for about 24 h at 4°C. The observation suggests that R1 is likely to be unstable at room temperature.The HPLC-UV chromatogram of the rat urine collected from 0 to 6 h after administration of non-labeled YM872 also showed a major peak corresponding to the parent compound and small peaks corresponding to the metabolites, R1 and R2. These metabolites were semi-purified by repeated preparative HPLC as described in the experimental section, followed by the elucidation of their structures.Based on LC-MS analysis, the parent compound had a protonated molecule at m/z 332. MS/MS analysis of the protonated molecule revealed fragment ions at m/z 286 and 242, which were derived from the loss of NO 2 and the loss of NO 2 and CO 2 , r...

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Neuroprotective effects of an AMPA receptor antagonist YM872 in a rat transient middle cerebral artery occlusion model

Cited by 33 publications

References 20 publications

5′-Alkyl-benzothiadiazides: A New Subgroup of AMPA Receptor Modulators with Improved Affinity

5′-Alkyl-benzothiadiazides: A New Subgroup of AMPA Receptor Modulators with Improved Affinity

Clinical trials for cytoprotection in stroke

Application of LC-NMR for Characterization of Rat Urinary Metabolites of Zonampanel Monohydrate (YM872)

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