Discovery of PF-06835919: A Potent Inhibitor of Ketohexokinase (KHK) for the Treatment of Metabolic Disorders Driven by the Overconsumption of Fructose

J Med Chem. 2020 Nov 25;63(22):13546-13560. doi: 10.1021/acs.jmedchem.0c00944. Epub 2020 Sep 27.

Abstract

Increased fructose consumption and its subsequent metabolism have been implicated in metabolic disorders such as nonalcoholic fatty liver disease and steatohepatitis (NAFLD/NASH) and insulin resistance. Ketohexokinase (KHK) converts fructose to fructose-1-phosphate (F1P) in the first step of the metabolic cascade. Herein we report the discovery of a first-in-class KHK inhibitor, PF-06835919 (8), currently in phase 2 clinical trials. The discovery of 8 was built upon our originally reported, fragment-derived lead 1 and the recognition of an alternative, rotated binding mode upon changing the ribose-pocket binding moiety from a pyrrolidinyl to an azetidinyl ring system. This new binding mode enabled efficient exploration of the vector directed at the Arg-108 residue, leading to the identification of highly potent 3-azabicyclo[3.1.0]hexane acetic acid-based KHK inhibitors by combined use of parallel medicinal chemistry and structure-based drug design.

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Discovery / methods*
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Fructokinases / antagonists & inhibitors*
  • Fructokinases / metabolism*
  • Fructose / administration & dosage
  • Fructose / adverse effects*
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology
  • Humans
  • Insulin Resistance / physiology
  • Male
  • Metabolic Diseases / chemically induced
  • Metabolic Diseases / drug therapy
  • Metabolic Diseases / enzymology*
  • Protein Structure, Secondary
  • Rats
  • Rats, Wistar

Substances

  • Enzyme Inhibitors
  • Fructose
  • Fructokinases
  • ketohexokinase