text: Capsazepine (fig. 4a), the first competitive vanilloid antagonist, reported by Novartis group, was aimed at assessing the effect of conformational constraint on the lipophilic C-region of capsaicin. In capsazepine the amide bond of the capsaicin is replaced by a thiourea moiety and a propylidene linker between the aromatic vanillyl 2-carbon A ring and the B-linker amide nitrogen forces the aromatic ring in an orthogonal orientation with respect to the thiourea bond. This constraint has long been considered as the distinctive characteristic of vanilloid antagonism. Capsazepine competes for the capsaicin-binding site on TRPV1 however, due to low metabolic stability and poor pharmacokinetic properties the compound did not reach into clinical development. It was observed later on that this tether was not critical for activity as powerful antagonists free from this structural feature were developed, with 1,3-di(arylalkyl)thioureas emerging as one of the most promising non-vanilloid class of TRPV1 antagonist showing excellent therapeutical potential in pain regulation. Within these compounds, the replacement of the guaiacyl moiety of capsaicinoids with a 3-fluoro-4-sulfonylamido group found critical to revert activity. This led to the design of C-region moiety mimicked on RTX, led to compound seen in figure 4b, that showed excellent analgesic activity in mice. An alternative optimization of the lipophilic C region led to JYL1421 (fig. 4c), another promising clinical candidate.