Synthesis and SAR of novel 2-arylthiazolidinones as selective analgesic N-type calcium channel blockers

A series of new N-type (Cav2.2) calcium channel blockers derived from the ‘hit’ structures 2-(3-bromo-4-fluorophenyl)-3-(2-pyridin-2-ylethyl)thiazolidin-4-one 9 and its 2-[4-(4-bromophenyl)pyridin-3-yl]-3-isobutyl analogue 10 is described. Extensive SAR studies using a range of synthetic approaches resulted in novel, patented compounds with IC50 values of up to 0.2 μM in an in vitro IMR32 assay, and selectivities for N/L of up to 30-fold. The new compounds described have potential in treatment of neuropathic pain.

Graphical abstractA series of new N-type (Cav2.2) calcium channel blockers derived from the ‘hit’ structures 9 and 10 is described. Extensive SAR studies using a range of synthetic approaches resulted in novel, patented compounds with IC50 values of up to 0.2 μM in an in vitro IMR32 assay, and selectivities for N/L of up to 30-fold. The new compounds described have potential in treatment of neuropathic pain.Figure optionsDownload full-size imageDownload as PowerPoint slide