Disease relevance of BMS-204352

• Administration of 0.03 mg/kg BMS-204352 significantly reduced cerebral edema in the ipsilateral thalamus (P < 0.05) [1].
• The authors evaluated the effects of postinjury systemic administration of the maxi-K channel opener, BMS-204352, on behavioral and histologic outcome after lateral fluid percussion (FP) traumatic brain injury (TBI) in the rat [1].
• The N-glucuronide of BMS-204352 was stable up to 24 h at 37 degrees C in the incubations at different pH values (3.0, 7.4, and 9.0) and with glucuronidases from Escherichia coli and Helix pomatia [2].
• One of its enantiomers, BMS-204352 (MaxiPost), is undergoing clinical evaluation for efficacy in patients with suspected acute stroke [3].

High impact information on BMS-204352

• In rat models of permanent large-vessel stroke, BMS-204352 provided significant levels of cortical neuroprotection when administered two hours after the onset of occlusion, but had no effects on blood pressure or cerebral blood flow [4].
• The maxi-K channel opener BMS-204352 attenuates regional cerebral edema and neurologic motor impairment after experimental brain injury [1].
• Administration of 0.1 mg/kg BMS-204352 improved neurologic motor function at 1 and 2 weeks postinjury (P < 0.05) and reduced the extent of cerebral edema in the ipsilateral hippocampus, thalamus, and adjacent cortex (P < 0.05) [1].
• In patch-clamp electrophysiology on cell lines expressing Kv7 channel subtypes, Maxipost (BMS-204352) exerted positive modulation of all neuronal Kv7 channels, whereas its R-enantiomer was a negative modulator [5].
• At GABA(A) receptors (alpha1beta2gamma2s and alpha2beta2gamma2s) expressed in Xenopus oocytes, BMS-204352 was a negative modulator, and the R-enantiomer was a positive modulator [5].

Biological context of BMS-204352

• Finally, a pronounced slowing of the deactivation kinetics was induced in particular by BMS-204352 [6].
• The current study was designed to evaluate the dose proportionality and pharmacokinetics of BMS-204352 in rats [7].
• In conclusion, the potential for a drug-drug interaction due to alterations in protein binding with BMS-204352 is unlikely [8].
• As dose increased from 5 to 10 mg/kg, both BMS-204352 C(max) and AUC values increased in plasma and brain, somewhat greater in proportion to the increment in dose [9].
• Bioavailability and extent of absorption data suggest evidence of first pass metabolism of BMS-204352 in the rat and dog [10].

Anatomical context of BMS-204352

• After IA administration of radiolabeled BMS-204352 to rats, ca. 5.9 and 85% of radioactivity was recovered within 7 days in urine and feces, respectively; corresponding recoveries after PO dosing were 4.5 and 99.5%, respectively [10].
• BMS-204352 crossed the blood-brain barrier with brain-to-plasma (B/P) ratios of approximately 7-11 [9].
• In an open, parallel fashion, sixteen rats per gender received a single intraarterial dose of BMS-204352 as a 3-min infusion into the carotid artery at 0.4, 2.0, 5.0 and 10.0 mg/kg dose levels [7].
• Rats (3 animals/group/time point) received a single intravenous dose of BMS-204352 as 5 mg/kg bolus, 5 mg/kg 30 min infusion, 5 mg/kg 60 min infusion, and 10 mg/kg bolus dose, into the jugular vein [9].
• In an open, three-way crossover study, three beagle dogs received a single intravenous dose of BMS-204352 as a 6-min infusion into the femoral vein at 0.4, 0.9, and 2.0 mg/kg dose levels [11].

Associations of BMS-204352 with other chemical compounds

• We have employed a cinchona alkaloid/Selectfluor-mediated enantioselective fluorination of the oxindole 2 to achieve the first enantioslective synthesis of BMS-204352 (MaxiPost, S-1), an effective opener of maxi-K channels [12].
• KCNQ4 channel activation by BMS-204352 and retigabine [6].
• The M-current blocker linopirdine inhibited the baseline current, as well as the BMS-204352-induced activation of the KCNQ4 channels [6].
• 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one (NS-1619) and (3S)-(+)-(5-chloro-2-methoxyphenyl-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one (BMS 204352) maxi-K channel openers significantly elevated CK2 activities that were reversible by iberiotoxin [13].

Gene context of BMS-204352

• Activation of KCNQ5 channels stably expressed in HEK293 cells by BMS-204352 [14].
• At 10 microM, BMS-204352 increased the steady state current at -30 mV by 12-fold, in contrast to the 2-fold increase observed for the other KCNQ channels [Schrøder et al., 2001] [14].
• These results suggest that the novel maxi-K channel opener BMS-204352 may be selectively beneficial in the treatment of experimental TBI [1].
• Two compounds, BMS-204352 and retigabine, presently in clinical trials for the treatment of stroke and epilepsy, respectively, have been proposed to exert their protective action via an activation of potassium channels [6].
• Protein binding of BMS-204352 was determined in sera from several species, namely, rat, monkey, dog, and human [8].

Analytical, diagnostic and therapeutic context of BMS-204352

• Oxindole 1 (BMS-204352; MaxiPost) can be isolated using chiral HPLC or prepared by employing chiral resolution [15].
• Blood, urine, and feces samples were collected and analyzed for unchanged BMS-204352 (plasma) using a validated LC/MS assay and for total radioactivity (plasma, urine, feces) using liquid scintillation counting [10].

References