Oxadiazolone bioisosteres of pregabalin and gabapentin.
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.
Wustrow
David J
DJ
Pfizer Global Research and Development, Groton, CT 06340, USA.
Belliotti
Thomas R
TR
Capiris
Thomas
T
Kneen
Clare O
CO
Bryans
Justin S
JS
Field
Mark J
MJ
Williams
Dic
D
El-Kattan
Ayman
A
Buchholz
Lisa
L
Kinsora
Jack J
JJ
Lotarski
Susan M
SM
Vartanian
Mark G
MG
Taylor
Charles P
CP
Donevan
Sean D
SD
Thorpe
Andrew J
AJ
Schwarz
Jacob B
JB
D000588:Amines; D000818:Animals; D001921:Brain / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D000077206:Gabapentin; D050810:Octamer Transcription Factors; D027361:Organic Anion Transporters; D010003:Osteoarthritis / Q000188:drug therapy*; D010069:Oxadiazoles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D000069583:Pregabalin; D051381:Rats; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives*
D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D050810:Octamer Transcription Factors; D027361:Organic Anion Transporters; D010069:Oxadiazoles; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin