Abstract
A variety of water-soluble prodrugs of BMS-191011 was synthesized and evaluated for solution state stability and rate of conversion to BMS-191011 in rat and human plasma. The deoxycarnitine ester prodrug (11c) was selected for clinical evaluation based on its superior chemical stability, crystallinity and cleavage to BMS-191011 in human plasma.
MeSH terms
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Animals
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Betaine / analogs & derivatives*
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Blood / metabolism
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Carnitine*
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Crystallization
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Dose-Response Relationship, Drug
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Drug Stability
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Heterocyclic Compounds, 3-Ring / chemical synthesis*
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Heterocyclic Compounds, 3-Ring / metabolism
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Heterocyclic Compounds, 3-Ring / pharmacokinetics
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Humans
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Neuroprotective Agents / chemical synthesis*
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Neuroprotective Agents / metabolism
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Neuroprotective Agents / pharmacokinetics*
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Oxadiazoles
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Potassium Channels / agonists*
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Prodrugs / chemical synthesis*
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Prodrugs / metabolism*
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Prodrugs / pharmacokinetics
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Rats
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Solubility
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Stroke / drug therapy*
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Structure-Activity Relationship
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Water
Substances
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3-((5-chloro-2-hydroxyphenyl)methyl)-5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2(3H)-one
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Heterocyclic Compounds, 3-Ring
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Neuroprotective Agents
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Oxadiazoles
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Potassium Channels
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Prodrugs
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Water
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Betaine
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gamma-butyrobetaine
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Carnitine