Synthesis and Biological Characterization of a 17β Hydroxysteroid Dehydrogenase Type 10 (17β-HSD10) Inhibitor

Alzheimer’s Disease (AD) is estimated to affect over 55 million people across the world. Small molecule treatment options are limited to symptom management with no impact on disease progression. The need for new protein targets and small molecule hit compounds is unmet and urgent. Hydroxysteroid 17-beta dehydrogenase 10 (17β-HSD10) is a mitochondrial enzyme know to bind amyloid beta, a hallmark of AD, and potentiate its toxicity to neurons. Identification of small molecules capable of interacting with 17β-HSD10 may drive drug discovery efforts for AD. The screening compound BCC0100281 (1), was previously identified as an inhibitor of 17β-HSD10. Herein we report the first synthetic access to the hit compound following a convergent pathway starting from simple heterocycle building blocks. The compound was found to be toxic to ‘neuron-like’ cells. However, assay of synthetic intermediates identified novel scaffolds with effect to rescue amyloid beta-induced cytotoxicity, showcasing the power of organic synthesis and medicinal chemistry to optimize hit compounds to identify potential leads.