title: Oxadiazolone bioisosteres of pregabalin and gabapentin.
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.
authors.affiliation: Pfizer Global Research and Development, Groton, CT 06340, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Wustrow
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Belliotti
authors.forename: Thomas
authors.initials: T
authors.lastname: Capiris
authors.forename: Clare O
authors.initials: CO
authors.lastname: Kneen
authors.forename: Justin S
authors.initials: JS
authors.lastname: Bryans
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Field
authors.forename: Dic
authors.initials: D
authors.lastname: Williams
authors.forename: Ayman
authors.initials: A
authors.lastname: El-Kattan
authors.forename: Lisa
authors.initials: L
authors.lastname: Buchholz
authors.forename: Jack J
authors.initials: JJ
authors.lastname: Kinsora
authors.forename: Susan M
authors.initials: SM
authors.lastname: Lotarski
authors.forename: Mark G
authors.initials: MG
authors.lastname: Vartanian
authors.forename: Charles P
authors.initials: CP
authors.lastname: Taylor
authors.forename: Sean D
authors.initials: SD
authors.lastname: Donevan
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Thorpe
authors.forename: Jacob B
authors.initials: JB
authors.lastname: Schwarz
mesh_terms: 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*
chemical_list: D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D050810:Octamer Transcription Factors; D027361:Organic Anion Transporters; D010069:Oxadiazoles; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin