Synthesis of <sup>3</sup>H and <sup>14</sup>C labeled (S)‐3‐(5‐chloro‐2‐methoxyphenyl)‐1,3‐dihydro‐3‐fluoro‐6‐(trifluoromethyl)‐2H‐indol‐2‐one, maxipost™. An agent for post‐stroke neuroprotection

Dischino, Douglas D.; Gribkoff, Valentin K.; Hewawasam, Piyasena; Luke, G. M.; Rinehart, J. Kent; Spears, Tony; Starrett, John E.

doi:10.1002/jlcr.652

Cited by 13 publications

(14 citation statements)

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“…14 C]BMS-204352 (5 Ci/mg, radiochemical purity 99.5%), des-fluoro BMS-204352 lysine adduct (BMS-349821, 98% pure), and [ 13 CD 3 ]BMS-204352 (internal standard for LC/MS/MS analysis) were synthesized at Bristol-Myers Squibb (Dischino et al, 2003;Zhang et al, 2003).…”

Section: Chemicals [mentioning

confidence: 99%

Metabolism, Pharmacokinetics, and Protein Covalent Binding of Radiolabeled Maxipost (Bms-204352) in Humans

Zhang¹,

Krishna²,

Wang³

et al. 2004

Drug Metab Dispos

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MaxiPost [(3S)-(؉)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one); BMS-204352] is an investigational maxi-K channel opener to treat ischemic stroke. This study reports the disposition, metabolism, pharmacokinetics, and protein covalent binding of 14 C-labeled MaxiPost in healthy male volunteers as well as in dogs and rats. After each human subject received a single dose of 10 mg 14 C-labeled BMS-204352 (50 Ci) as a 5-ml intravenous infusion lasting 5 min, the plasma radioactivity concentrations showed a unique profile, wherein the concentration appeared to increase initially, followed by a terminal decline. The mean terminal t 1/2 of plasma radioactivity (259 h) was prolonged compared with that of unchanged parent (37 h). Furthermore, the extractability of radioactivity in plasma decreased over time, reaching approximately 20% at 4 h after dosing. The unextractable radioactivity was covalently bound to plasma proteins through a des-fluoro-des-methyl BMS-204352 lysine adduct. Unchanged BMS-204352 and minor metabolites were identified in plasma extract following protein precipitation. The recovery of the radioactive dose in urine and feces was nearly complete in 14-day collections (approximately 37% in urine and 60% in feces). The N-glucuronide of the parent was the prominent metabolite in urine (16.5% of dose), whereas the parent was a major drug-related component in feces (11% of dose). Similar disposition, metabolism, pharmacokinetic, and protein covalent binding properties of 14 C-labeled BMS-204352 were observed in humans, dogs, and rats.Stroke is a major cause of death and long-term disability, affecting more than 700,000 people in the United States annually (Williams et al., 1999). Acute ischemic stroke is the most common form, producing pathologically fatal levels of intracellular calcium (Ca 2ϩ ) in neurons at risk. Maxi-K channels are large-conductance voltage-and Ca 2ϩ -activated K ϩ channel proteins (Chang et al., 1997). BMS-204352, chemically designated as (3S)-(ϩ)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one), is a maxi-K channel opener . This compound has the potential to prevent and treat ischemic stroke. The fluoro-oxyindole, BMS-204352, provided significant levels of cortical neuroprotection in rat models of stroke by augmenting an endogenous mechanism for regulating Ca 2ϩ entry and membrane potential to protect the neurons (Cheney et al., 2001;Gribkoff et al., 2001).Metabolism appeared to be predominant in the disposition of BMS-204352 in rats and dogs (Krishna et al., 2002d). Following an intraarterial infusion of [ 14 C]BMS-204352 to rats (6 mg/kg) and dogs (2 mg/kg), the AUC values of the unchanged BMS-204352 represented only a very small fraction of the plasma radioactivity. Radioactivity was primarily excreted in the feces (more than 85% of administered dose over a 7-day collection period). Within an hour of dosing rats with [14 C]BMS-204352, over two-thirds of the radioactivity in plasma is covalently ...

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Section: Chemicals [mentioning

confidence: 99%

Metabolism, Pharmacokinetics, and Protein Covalent Binding of Radiolabeled Maxipost (Bms-204352) in Humans

Zhang¹,

Krishna²,

Wang³

et al. 2004

Drug Metab Dispos

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“…1) was synthesized at Bristol-Myers Squibb Co. (Stamford, CT) (Dischino et al, 2003). Ammonium acetate, Tris-HCl, UDPGA, phenolphthalein glucuronic acid, glycine, and glucuronidase (type H-1 from Helix pomatia, 486,000 units/g, type VII-A from Escherichia coli, 1000 units per vial) were purchased from Sigma-Aldrich (St. Louis, MO).…”

Section: Materials [mentioning

confidence: 99%

AMIDE N-GLUCURONIDATION OF MAXIPOST CATALYZED BY UDP-GLUCURONOSYLTRANSFERASE 2B7 IN HUMANS

Zhang¹,

Zhao²,

Roongta³

et al. 2004

Drug Metab Dispos

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“…1 (1a)), 3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one, and its enantiomer ( Fig. 1 (1b)) were both synthesized at BristolMyers Squibb Company (New Brunswick, NJ) [27]. Lithium chloride, ammonium acetate, glacial acetic acid, methanol, acetonitrile, and (+)-5-fluorodeoxyuridine ( Fig.…”

Section: Methodsmentioning

confidence: 99%

Chiral purity assay for Flindokalner using tandem mass spectrometry: Method development, validation, and benchmarking

Young

Cooks

Madden

et al. 2007

Journal of Pharmaceutical and Biomedical Analysis

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Synthesis of ³H and ¹⁴C labeled (S)‐3‐(5‐chloro‐2‐methoxyphenyl)‐1,3‐dihydro‐3‐fluoro‐6‐(trifluoromethyl)‐2H‐indol‐2‐one, maxipost™. An agent for post‐stroke neuroprotection

Cited by 13 publications

References 5 publications

Metabolism, Pharmacokinetics, and Protein Covalent Binding of Radiolabeled Maxipost (Bms-204352) in Humans

Metabolism, Pharmacokinetics, and Protein Covalent Binding of Radiolabeled Maxipost (Bms-204352) in Humans

AMIDE N-GLUCURONIDATION OF MAXIPOST CATALYZED BY UDP-GLUCURONOSYLTRANSFERASE 2B7 IN HUMANS

Chiral purity assay for Flindokalner using tandem mass spectrometry: Method development, validation, and benchmarking

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Synthesis of 3H and 14C labeled (S)‐3‐(5‐chloro‐2‐methoxyphenyl)‐1,3‐dihydro‐3‐fluoro‐6‐(trifluoromethyl)‐2H‐indol‐2‐one, maxipost™. An agent for post‐stroke neuroprotection

Cited by 13 publications

References 5 publications

Metabolism, Pharmacokinetics, and Protein Covalent Binding of Radiolabeled Maxipost (Bms-204352) in Humans

Metabolism, Pharmacokinetics, and Protein Covalent Binding of Radiolabeled Maxipost (Bms-204352) in Humans

AMIDE N-GLUCURONIDATION OF MAXIPOST CATALYZED BY UDP-GLUCURONOSYLTRANSFERASE 2B7 IN HUMANS

Chiral purity assay for Flindokalner using tandem mass spectrometry: Method development, validation, and benchmarking

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Synthesis of ³H and ¹⁴C labeled (S)‐3‐(5‐chloro‐2‐methoxyphenyl)‐1,3‐dihydro‐3‐fluoro‐6‐(trifluoromethyl)‐2H‐indol‐2‐one, maxipost™. An agent for post‐stroke neuroprotection