Design and synthesis of novel fluorene derivatives as inhibitors of pyruvate dehydrogenase kinase

Bioorg Med Chem Lett. 2024 Sep 1:109:129839. doi: 10.1016/j.bmcl.2024.129839. Epub 2024 Jun 5.

Abstract

Activation of pyruvate dehydrogenase (PDH) by inhibition of pyruvate dehydrogenase kinase (PDHK) has the potential for the treatment of diabetes mellitus and its complications, caused by the malfunction of the glycolytic system and glucose oxidation. In this paper, we describe the identification of novel PDHK inhibitors with a fluorene structure. High-throughput screening using our in-house library provided compound 6 as a weak inhibitor that occupied the allosteric lipoyl group binding site in PDHK2. Structure-based drug design (SBDD) while addressing physicochemical properties succeeded in boosting inhibitory activity approximately 700-fold. Thus obtained compound 32 showed favorable pharmacokinetics profiles supported by high membrane permeability and metabolic stability, and exhibited activation of PDH in rat livers and a glucose lowering effect in Zucker fatty rats.

Keywords: Fluorene; Pyruvate dehydrogenase activation; Pyruvate dehydrogenase kinase inhibitor.

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Fluorenes* / chemical synthesis
  • Fluorenes* / chemistry
  • Fluorenes* / pharmacology
  • Humans
  • Molecular Structure
  • Protein Kinase Inhibitors* / chemical synthesis
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Protein Serine-Threonine Kinases* / antagonists & inhibitors
  • Protein Serine-Threonine Kinases* / metabolism
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase* / antagonists & inhibitors
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase* / metabolism
  • Rats
  • Rats, Zucker*
  • Structure-Activity Relationship

Substances

  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Fluorenes
  • Protein Kinase Inhibitors
  • Protein Serine-Threonine Kinases
  • fluorene