Development of Potent and Selective Inhibitors of Aldo-Keto Reductase 1C3 (Type 5 17β-hydroxysteroid Dehydrogenase) Based on N-phenyl-aminobenzoates and Their Structure-Activity Relationships

J Med Chem. 2012 Mar 8;55(5):2311-23. doi: 10.1021/jm201547v. Epub 2012 Feb 15.

Abstract

Aldo-keto reductase 1C3 (AKR1C3; type 5 17β-hydroxysteroid dehydrogenase) is overexpressed in castration resistant prostate cancer (CRPC) and is implicated in the intratumoral biosynthesis of testosterone and 5α-dihydrotestosterone. Selective AKR1C3 inhibitors are required because compounds should not inhibit the highly related AKR1C1 and AKR1C2 isoforms which are involved in the inactivation of 5α-dihydrotestosterone. NSAIDs, N-phenylanthranilates in particular, are potent but nonselective AKR1C3 inhibitors. Using flufenamic acid, 2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid, as lead compound, five classes of structural analogues were synthesized and evaluated for AKR1C3 inhibitory potency and selectivity. Structure-activity relationship (SAR) studies revealed that a meta-carboxylic acid group relative to the amine conferred pronounced AKR1C3 selectivity without loss of potency, while electron withdrawing groups on the phenylamino B-ring were optimal for AKR1C3 inhibition. Lead compounds did not inhibit COX-1 or COX-2 but blocked the AKR1C3 mediated production of testosterone in LNCaP-AKR1C3 cells. These compounds offer promising leads toward new therapeutics for CRPC.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 20-Hydroxysteroid Dehydrogenases / antagonists & inhibitors
  • 3-Hydroxysteroid Dehydrogenases / antagonists & inhibitors*
  • 3-Hydroxysteroid Dehydrogenases / genetics
  • 3-Hydroxysteroid Dehydrogenases / metabolism
  • Aldo-Keto Reductase Family 1 Member C3
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cyclooxygenase 1 / metabolism
  • Cyclooxygenase 2 / metabolism
  • Cyclooxygenase Inhibitors / chemical synthesis
  • Cyclooxygenase Inhibitors / chemistry
  • Cyclooxygenase Inhibitors / pharmacology
  • Fenamates / chemical synthesis*
  • Fenamates / chemistry
  • Fenamates / pharmacology
  • Humans
  • Hydroxyprostaglandin Dehydrogenases / antagonists & inhibitors*
  • Hydroxyprostaglandin Dehydrogenases / genetics
  • Hydroxyprostaglandin Dehydrogenases / metabolism
  • Hydroxysteroid Dehydrogenases / antagonists & inhibitors
  • Isoenzymes / antagonists & inhibitors
  • Male
  • Prostatic Neoplasms / drug therapy
  • Structure-Activity Relationship
  • Testosterone / antagonists & inhibitors
  • Testosterone / biosynthesis

Substances

  • Antineoplastic Agents
  • Cyclooxygenase Inhibitors
  • Fenamates
  • Isoenzymes
  • Testosterone
  • 3-Hydroxysteroid Dehydrogenases
  • Hydroxysteroid Dehydrogenases
  • 20-Hydroxysteroid Dehydrogenases
  • 3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase
  • Hydroxyprostaglandin Dehydrogenases
  • AKR1C2 protein, human
  • AKR1C3 protein, human
  • Aldo-Keto Reductase Family 1 Member C3
  • Cyclooxygenase 1
  • Cyclooxygenase 2