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 BI-3231. Through high-throughput
screening (HTS), using estradiol as substrate, compound 1 was identified and selected for subsequent optimization resulting
in compound 45 (BI-3231). In addition to the characterization
of compound 45 for its functional, physicochemical, and
drug metabolism and pharmacokinetic (DMPK) properties, NAD+ dependency was investigated. To support Open Science, the chemical
HSD17B13 probe BI-3231 will be available to the scientific
community for free via the opnMe platform,
and thus can help to elucidate the pharmacology of HSD17B13.