학술논문
Discovery of a Novel Potent and Selective HSD17B13 Inhibitor, BI-3231, a Well-Characterized Chemical Probe Available for Open Science
Document Type
Article
Author
Thamm, Sven; Willwacher, Marina K.; Aspnes, Gary E.; Bretschneider, Tom; Brown, Nicholas F.; Buschbom-Helmke, Silke; Fox, Thomas; Gargano, Emanuele M.; Grabowski, Daniel; Hoenke, Christoph; Matera, Damian; Mueck, Katja; Peters, Stefan; Reindl, Sophia; Riether, Doris; Schmid, Matthias; Tautermann, Christofer S.; Teitelbaum, Aaron M.; Trünkle, Cornelius; Veser, Thomas; Winter, Martin; Wortmann, Lars
Source
Journal of Medicinal Chemistry; February 2023, Vol. 66 Issue: 4 p2832-2850, 19p
Subject
Language
ISSN
00222623; 15204804
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 1was identified and selected for subsequent optimization resulting in compound 45 (BI-3231). In addition to the characterization of compound 45for its functional, physicochemical, and drug metabolism and pharmacokinetic (DMPK) properties, NAD+dependency was investigated. To support Open Science, the chemical HSD17B13 probe BI-3231will be available to the scientific community for free via the opnMe platform, and thus can help to elucidate the pharmacology of HSD17B13.