Discovery of a Novel Potent and Selective HSD17B13 Inhibitor, BI-3231, a Well-Characterized Chemical Probe Available for Open Science.

Genome-wide association studies in patients revealed HSD17B13 as a potential new target for the treatment of nonalcoholic steatohepatitis (NASH) and other liver diseases. However, the physiological function and the disease-relevant substrate of HSD17B13 remain unknown. In addition, no suitable chemical probe for HSD17B13 has been published yet. Herein, we report the identification of the novel potent and selective HSD17B13 inhibitor . Through high-throughput screening (HTS), using estradiol as substrate, compound was identified and selected for subsequent optimization resulting in compound . In addition to the characterization of compound for its functional, physicochemical, and drug metabolism and pharmacokinetic (DMPK) properties, NAD dependency was investigated. To support Open Science, the chemical HSD17B13 probe will be available to the scientific community for free via the opnMe platform, and thus can help to elucidate the pharmacology of HSD17B13.