Substituted fused bicyclic pyrrolizinones as potent, orally bioavailable hNK1 antagonists

Previous work on human NK1 (hNK1) antagonists in which the core of the structure is a 5,5-fused pyrrolizinone has been disclosed. The structural–activity-relationship studies on simple α- and β-substituted compounds of this series provided several potent and bioavailable hNK1 antagonists that displayed excellent brain penetration as observed by their good efficacy in the gerbil foot-tapping (GFT) model assay. Several of these compounds exhibited 100% inhibition of the foot-tapping response at 0.1 and 24h with ID50’s of less than 1mpk. One particular α-substituted compound (2b) had an excellent pharmacokinetic profile across preclinical species with reasonable in vivo functional activity and minimal ancillary activity.