Moving out of CF₃ -Land: Synthesis, Receptor Affinity, and in silico Studies of NK1 Receptor Ligands Containing a...

The NK1 receptor (NK1R) is a molecular target for both approved and experimental drugs intended for a variety of conditions, including emesis, pain, and cancers. While contemplating modifications to the typical NK1R pharmacophore, we wondered whether the CF₃ groups common for many NK1R ligands, could be replaced with some other moiety. Our attention was drawn by the SF₅ group, and so we designed, synthesized, and tested ten novel SF₅ -containing compounds for NK1R affinity. All analogues exhibit detectable NK1R binding, with the best of them, compound 5 a, (3-bromo-5-(pentafluoro-λ⁶ -sulfanyl)benzyl acetyl-L-tryptophanate) binding only slightly worse (IC₅₀ =34.3 nM) than the approved NK1R-targeting drug, aprepitant (IC₅₀ =27.7 nM). Molecular docking provided structural explanation of SAR. According to our analysis, the SF₅ group in our compounds occupies a position similar to that of one of the CF₃ groups of aprepitant as found in the crystal structure. Additionally, we checked whether the docking scoring function or energies derived from Fragment Molecular Orbital quantum chemical calculations may be helpful in explaining and predicting the experimental receptor affinities for our analogues. Both these methods produce moderately good results. Overall, this is the first demonstration of the utility of the SF₅ group in the design of NK1R ligands.