Discovery of a benzimidazole series of ADAMTS-5 (aggrecanase-2) inhibitors by scaffold hopping.

We describe a medicinal chemistry approach to generate a series of benzimidazoles bearing thiazolidin-4-one using scaffold hopping from thiazole 1, our previously described thiazole. Our goal was to discover a potent and permeable small-molecule ADAMTS-5 inhibitor. The results suggest that small compound 22 shows promise as a potent small-molecule ADAMTS-5 inhibitor with good permeability.

A series of thiazole derivatives bearing thiazolidin-4-one as non-competitive ADAMTS-5 (aggrecanase-2) inhibitors.

A series of thiazole bearing thiazolidin-4-one was discovered via high-throughput screening as non-competitive inhibitors of ADAMTS-5. Compound 31 appeared to give the best ADAMTS-5 inhibition and good selectivity over other metalloproteases.