The pentafluorosulfanyl group in cannabinoid receptor ligands: synthesis and comparison with trifluoromethyl and tert-butyl analogues.

An array of cannabinoid ligands, bearing meta- and para-substituted pentafluorosulfanyl (SF₅) aniline groups in position 3 of the pyrazole ring, was efficiently synthesised and compared with the exact trifluoromethyl and tert-butyl analogues. In general, the SF₅ substituted ligands showed higher lipophilicity (i.e. logP values) than the CF₃ counterparts and lower lipophilicity than the tert-butyl ones. In terms of pharmacological activity, SF₅ pyrazoles generally showed slightly higher or equivalent CB₁ receptor affinity (K_i), always in the nanomolar range, and selectivity towards the CB₂ relative to both CF₃ and tert-butyl analogues. Functional β-arrestin recruitment assays were used to determine equilibrium dissociation constants (K_b) and showed that all of the tested SF₅ and CF₃ compounds are CB₁ neutral antagonists. These results confirm the possibility of successfully using an aromatic SF₅ group as a stable, synthetically accessible and effective bioisosteric analogue of the electron-withdrawing CF₃ group, and possibly also of bulky aliphatic groups, for drug discovery and development applications.