Design and campaign synthesis of piperidine- and thiazole-based histone deacetylase inhibitors

A lead benzamide, 3, was identified as a potent and low molecular weight histone deacetylase (HDAC) inhibitor. Optimization led to 16d, demonstrating an excellent balance of efficacy and non-efficacy properties, along with very desirable in vivo DMPK. The final compounds presented are >1000-fold more potent than the initial screen hit, an improvement in potency which was achieved with a concomitant significant improvement in all the main non-efficacy properties.

Graphical abstractThe synthesis of the HDAC inhibitor 16d is reported. (HDAC1 enzyme pIC50 7.46. A549a xenograft efficacy at 12.5 mg/kg.)Figure optionsDownload full-size imageDownload as PowerPoint slide