Abstract
A series of oxadiazolone bioisosteres of pregabalin 1 and gabapentin 2 were prepared, and several were found to exhibit similar potency for the alpha(2)-delta subunit of voltage-gated calcium channels. Oxadiazolone 9 derived from 2 achieved low brain uptake but was nevertheless active in models of osteoarthritis. The high clearance associated with compound 9 was postulated to be a consequence of efflux by OAT and/or OCT, and was attenuated on co-administration with cimetidine or probenecid.
MeSH terms
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Amines*
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Animals
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Brain / metabolism
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Cyclohexanecarboxylic Acids*
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Drug Interactions
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Drug Therapy, Combination
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Gabapentin
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Octamer Transcription Factors
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Organic Anion Transporters
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Osteoarthritis / drug therapy*
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Oxadiazoles / chemistry*
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Oxadiazoles / pharmacology
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Oxadiazoles / therapeutic use*
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Pregabalin
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Rats
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gamma-Aminobutyric Acid / analogs & derivatives*
Substances
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Amines
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Cyclohexanecarboxylic Acids
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Octamer Transcription Factors
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Organic Anion Transporters
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Oxadiazoles
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Pregabalin
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gamma-Aminobutyric Acid
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Gabapentin