2. Academic Validation
  3. Discovery of BI-9787, a potent zwitterionic ketohexokinase inhibitor with oral bioavailability

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

  • Bioorg Med Chem Lett. 2024 Aug 22:112:129930. doi: 10.1016/j.bmcl.2024.129930.
Niklas Heine 1,  Alexander Weber 1,  Alexander Pautsch 1,  Dirk Gottschling 1,  Ingo Uphues 2,  Margit Bauer 1,  Rebecca Ebenhoch 1,  Aniket Magarkar 1,  Bernd Nosse 3,  Jörg Thomas Kley 4
Affiliations

Affiliations

  • 1 Boehringer Ingelheim Pharma GmbH & Co. KG, Global Medicinal Chemistry, Birkendorfer Straße 65, 88397 Biberach an der Riß, Germany.
  • 2 Boehringer Ingelheim Pharma GmbH & Co. KG, Cardiometabolic Diseases Research, Birkendorfer Straße 65, 88397 Biberach an der Riß, Germany.
  • 3 Boehringer Ingelheim Pharma GmbH & Co. KG, Global Medicinal Chemistry, Birkendorfer Straße 65, 88397 Biberach an der Riß, Germany; Boehringer Ingelheim International GmbH, Business Development & Licensing, Birkendorfer Straße 65, 88397 Biberach an der Riß, Germany.
  • 4 Boehringer Ingelheim Pharma GmbH & Co. KG, Global Medicinal Chemistry, Birkendorfer Straße 65, 88397 Biberach an der Riß, Germany. Electronic address: joerg.kley@boehringer-ingelheim.com.
PMID: 39179180 DOI: 10.1016/j.bmcl.2024.129930
Abstract

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.

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