Solid-phase synthesis of a library of amphipatic hydantoins. Discovery of new hits for TRPV1 blockade.

Some heterocyclic systems, called privileged scaffolds, appear frequently in bioactive products and marketed drugs. The combination of a recognized privileged scaffold (hydantoin) and a functional group with high incidence in bioactive molecules (guanidine) guided the design of a library of amphipatic compounds, which allowed the discovery of novel TRPV1 ion channel blockers. The library was synthesized by parallel solid-phase synthesis from an orthogonally protected resin-bound Lys-Lys skeleton. Key steps of the synthetic procedure were the construction of the hydantoin ring, by reaction of the N-terminal amino group with N,N-disuccinimidyl carbonate (DSC) and subsequent base-induced cyclization, and the guanidinylation of the C-terminal Lys side-chain after removal of the Alloc protecting-group. The preliminary biological studies have allowed the identification of some of the key structural features directing the blockage of capsaicin-induced Ca(2+) influx through TRPV1 channels, particularly, the strong preference showed for highly lipophilic acyl groups and substituted guanidine moieties. Active compounds based on this new pharmacophoric scaffold that display in vitro and in vivo inhibitory activity.