Development and Characterization of Novel and Selective Inhibitors of Cytochrome P450 CYP26A1, the Human Liver Retinoic Acid Hydroxylase

J Med Chem. 2016 Mar 24;59(6):2579-95. doi: 10.1021/acs.jmedchem.5b01780. Epub 2016 Mar 15.


Cytochrome P450 CYP26 enzymes are responsible for all-trans-retinoic acid (atRA) clearance. Inhibition of CYP26 enzymes will increase endogenous atRA concentrations and is an attractive therapeutic target. However, the selectivity and potency of the existing atRA metabolism inhibitors toward CYP26A1 and CYP26B1 is unknown, and no selective CYP26A1 or CYP26B1 inhibitors have been developed. Here the synthesis and potent inhibitory activity of the first CYP26A1 selective inhibitors is reported. A series of nonazole CYP26A1 selective inhibitors was identified with low nM potency. The lead compound 3-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolan-2-yl] phenyl}4-propanoic acid (24) had 43-fold selectivity toward CYP26A1 with an IC50 of 340 nM. Compound 24 and its two structural analogues also inhibited atRA metabolism in HepG2 cells, resulting in increased potency of atRA toward RAR activation. The identified compounds have potential to become novel treatments aiming to elevate endogenous atRA concentrations and may be useful as cotreatment with atRA to combat therapy resistance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Animals
  • Cell Line, Tumor
  • Cytochrome P-450 Enzyme System / drug effects*
  • Drug Design
  • Drug Resistance
  • Enzyme Induction
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Kinetics
  • Liver / drug effects
  • Liver / enzymology*
  • Rats
  • Retinoic Acid 4-Hydroxylase
  • Structure-Activity Relationship
  • Substrate Specificity
  • Tretinoin / metabolism


  • Enzyme Inhibitors
  • Isoenzymes
  • Tretinoin
  • Cytochrome P-450 Enzyme System
  • CYP26B1 protein, human
  • Cyp26b1 protein, rat
  • Retinoic Acid 4-Hydroxylase