Discovery of BI-9787, a potent zwitterionic ketohexokinase inhibitor with oral bioavailability

• Published in: Bioorganic & medicinal chemistry letters Vol. 112; pp. 129930 - 129938
• Main Authors: Heine, Niklas, Weber, Alexander, Pautsch, Alexander, Gottschling, Dirk, Uphues, Ingo, Bauer, Margit, Ebenhoch, Rebecca, Magarkar, Aniket, Nosse, Bernd, Kley, Jörg Thomas
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.11.2024; Elsevier
• Subjects: Chemistry; Chemistry, Medicinal; Chemistry, Organic; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; NAFLD; PPB; SAR; FaSSIF; FeS SIF; PAMPA; NASH; KHK; SFC; BICLAIM; Caco-2; Qh; PK; FRUCTOSE
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2024.129930

[Display omitted] •Potent zwitterionic KHK inhibitor BI-9787 is a novel in vitro/in vivo tool compound.•Introduction of a carboxylic acid moiety leads to high target selectivity.•Chameleonic properties enable high permeability and favorable oral rat PK.•BI-9787 and structurally close negative control BI-2817 are available on opnMe.com. Fructose metabolism by ketohexokinase (KHK) is implicated in a variety of metabolic disorders. KHK inhibition is a potential therapeutic strategy for the treatment of diseases including diabetes, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis. The first small-molecule KHK-inhibitors have entered clinical trials, but it remains unclear if systemic inhibition of KHK by small-molecules will eventually benefit patients. Here we report the discovery of BI-9787, a potent, zwitterionic KHK inhibitor characterized by high permeability and favorable oral rat pharmacokinetics. BI-9787 was identified by optimizing chemical starting points generated via a ligand-based virtual screening of Boehringer’s virtual library of synthetically accessible compounds (BICLAIM). It serves as a high-quality in vitro and in vivo tool compound for investigating the role of fructose metabolism in disease.