Oxadiazolone bioisosteres of pregabalin and gabapentin

  • Bioorg Med Chem Lett. 2009 Jan 1;19(1):247-50. doi: 10.1016/j.bmcl.2008.10.101.
David J Wustrow  1 ,  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
Affiliations
  • 1. Pfizer Global Research and Development, Groton, CT 06340, USA.
PMID: 19010672 DOI: 10.1016/j.bmcl.2008.10.101
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.