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

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

  • J Med Chem. 2023 Feb 23;66(4):2832-2850. doi: 10.1021/acs.jmedchem.2c01884.
Sven Thamm 1,  Marina K Willwacher 1,  Gary E Aspnes 1,  Tom Bretschneider 1,  Nicholas F Brown 2,  Silke Buschbom-Helmke 1,  Thomas Fox 1,  Emanuele M Gargano 1,  Daniel Grabowski 1,  Christoph Hoenke 1,  Damian Matera 2,  Katja Mueck 1,  Stefan Peters 1,  Sophia Reindl 1,  Doris Riether 1,  Matthias Schmid 1,  Christofer S Tautermann 1,  Aaron M Teitelbaum 1,  Cornelius Trünkle 1,  Thomas Veser 1,  Martin Winter 1,  Lars Wortmann 1
Affiliations

Affiliations

  • 1 Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach an der Riß, Germany.
  • 2 Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, Connecticut 06877-0368, United States.
PMID: 36727857 DOI: 10.1021/acs.jmedchem.2c01884
Abstract

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.

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