Pyrazolopyridazine alpha-2-delta-1 ligands for the treatment of neuropathic pain

Optimization of the novel alpha-2-delta-1 ligand 4 provided compounds 37 and 38 which have improved DMPK profiles, good in vivo analgesic activity and in vitro selectivity over alpha-2-delta-2. An in-house P-gp prediction programme and the MetaSite® software package were used to help solve the specific problems of high P-gp efflux and high in vivo clearance.