Abstract
Previous work on human NK 1 (hNK 1) 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 hNK 1 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 24 h with ID 50’s of less than 1 mpk. One particular α-substituted compound ( 2b) had an excellent pharmacokinetic profile across preclinical species with reasonable in vivo functional activity and minimal ancillary activity.
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