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Oxadiazolone bioisosteres of pregabalin and gabapentin |
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| Authors: | David J Wustrow Thomas R Belliotti Thomas Capiris Clare O Kneen Justin S Bryans Mark J Field Dic Williams Ayman El-Kattan Lisa Buchholz Jack J Kinsora Susan M Lotarski Mark G Vartanian Charles P Taylor Sean D Donevan Andrew J Thorpe Jacob B Schwarz |
| Institution: | 1. Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA;2. Sandwich Laboratories, Sandwich, Kent, CT13 9NJ, UK;3. St. Louis Laboratories, 700 Chesterfield Parkway W, Chesterfield, MO 63017, USA |
| Abstract: | A series of oxadiazolone bioisosteres of pregabalin 1 and gabapentin 2 were prepared, and several were found to exhibit similar potency for the α2-δ 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. |
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