Discovery of novel isothiazole inhibitors of the TrkA kinase: Structure–activity relationship, computer modeling, optimization, and identification of highly potent antagonists

The design, synthesis, and biological evaluation of potent inhibitors of the TrkA kinase is presented. A homology model is created to aid in the enhancement of potency and selectivity of isothiazole inhibitors found during a high-throughput screen. Three different syntheses are utilized to make diverse analogs within this series. Aminoheterocycles are found to be good urea surrogates, whereas bicyclic substituents on the C3 thio group were found to be extremely potent TrkA inhibitors in kinase and cell assays.

Graphical abstractThe design, synthesis, and biological evaluation of potent isothiazole inhibitors of the TrkA kinase is presented.Figure optionsDownload full-size imageDownload as PowerPoint slide