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

•We generated a series of benzimidazoles using scaffold hopping from thiazole.•We identified a potent ADAMTS-5 inhibitor using methyl-scanning.•We overcame poor permeability of thiazole derivative.

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.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide