Screening, synthesis, crystal structure, and molecular basis of 6-amino-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles as novel AKR1C3 inhibitors

Bioorg Med Chem. 2018 Dec 1;26(22):5934-5943. doi: 10.1016/j.bmc.2018.10.044. Epub 2018 Nov 3.


AKR1C3 is a promising therapeutic target for castration-resistant prostate cancer. Herein, an evaluation of in-house library discovered substituted pyranopyrazole as a novel scaffold for AKR1C3 inhibitors. Preliminary SAR exploration identified its derivative 19d as the most promising compound with an IC50 of 0.160 μM among the 23 synthesized molecules. Crystal structure studies revealed that the binding mode of the pyranopyrazole scaffold is different from the current inhibitors. Hydroxyl, methoxy and nitro group at the C4-phenyl substituent together anchor the inhibitor to the oxyanion site, while the core of the scaffold dramatically enlarges but partially occupies the SP pockets with abundant hydrogen bond interactions. Strikingly, the inhibitor undergoes a conformational change to fit AKR1C3 and its homologous protein AKR1C1. Our results suggested that conformational changes of the receptor and the inhibitor should both be considered during the rational design of selective AKR1C3 inhibitors. Detailed binding features obtained from molecular dynamics simulations helped to finally elucidate the molecular basis of 6-amino-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles as AKR1C3 inhibitors, which would facilitate the future rational inhibitor design and structural optimization.

Keywords: 1,4-Dihydropyrano[2,3-c]pyrazole; AKR1C3 inhibitors; Castration-resistant prostate cancer; Crystal structure; Synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldo-Keto Reductase Family 1 Member C3 / antagonists & inhibitors*
  • Aldo-Keto Reductase Family 1 Member C3 / metabolism
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Nitriles / chemical synthesis
  • Nitriles / chemistry
  • Nitriles / pharmacology*
  • Recombinant Proteins / metabolism
  • Structure-Activity Relationship


  • Enzyme Inhibitors
  • Nitriles
  • Recombinant Proteins
  • AKR1C3 protein, human
  • Aldo-Keto Reductase Family 1 Member C3