Discovery of a Novel Potent and Selective HSD17B13 Inhibitor, BI-3231, a Well-Characterized Chemical Probe Available for Open Science
Genome-wide association studies have identified HSD17B13 as a promising new target for treating nonalcoholic steatohepatitis (NASH) and other liver diseases. However, the physiological role and relevant substrates of HSD17B13 are still not fully understood, and no effective chemical probe for this target has been published. In this study, we present the discovery of a novel, potent, and selective HSD17B13 inhibitor, BI-3231.
Using high-throughput screening (HTS) with estradiol as the substrate, we identified compound 1, which underwent optimization to yield compound 45 (BI-3231). We characterized compound 45 in terms of its functional, physicochemical, and drug metabolism and pharmacokinetic (DMPK) properties, and we also investigated its dependency on NAD+.
In the spirit of Open Science, the chemical probe BI-3231 will be made freely available to the scientific community through the opnMe platform, facilitating further research into the pharmacology of HSD17B13.