Clinical compounds in the ChEMBL database (with five marketed, including two prodrugs) disclosed between 1992 and 2007. All NK-1 antagonists that reached Phase 3, and all discovered after 2002, are classified NPL or PNP (Figure ). Following aprepitant in 1995, all subsequent NK-1 antagonists employ a common 3,5-difluoromethylphenyl group and an additional phenyl ring. Aprepitant and netupitant bind to NK-1 in a similar mode, except for the pendant heterocycles that are part of their PNP motifs (triazolone and piperazine respectively, Figure ). However, both compounds are biologically comparable since they induce an identical intra-helical H-bonding network in the NK-1 structure, which might explain the advantageous insurmountable antagonism they exhibit. The NK-1 receptor stands out as a target where PNP occurrence in Clinical compounds (10/16, 63%) significantly exceeds than seen in Reference compounds (470/2158, 22%), with an odds ratio of 5.99 (p = 0.0006).