Inhibition of steroid sulphatase activity by tricyclic coumarin sulphamates

J Steroid Biochem Mol Biol. 2000 Dec 31;75(4-5):253-8. doi: 10.1016/s0960-0760(00)00178-3.

Abstract

The identification of the active pharmacophore required for potent inhibition of steroid sulphatase activity, i.e. an aryl-O-sulphamate structure, has led to the synthesis and testing of a large number of 1-4 ring-based inhibitors. 4-Methylcoumarin-7-O-sulphamate (COUMATE) was one of the first non-steroid based inhibitors identified. In an attempt to increase the potency of this class of inhibitor a series of tricyclic COUMATEs (665-6615 COUMATEs) have been synthesised and evaluated. Using placental microsomes as a source of oestrone sulphatase (E1-STS) the size of the third ring of the tricyclic COUMATEs was found to have a marked effect on inhibitor potency. Whereas 665- and 6615-COUMATEs had IC(50)s of 200 and 370 nM, respectively, the most potent inhibitor in vitro in this series was 6610 COUMATE with an IC(50) of 1 nM. Selected inhibitors were tested for their in vivo potency by administration of a single dose (0.1 or 1 mg/kg, p.o.) to female rats. Surprisingly, in vivo 6615 COUMATE proved to be the most active drug, inhibiting rat liver E1-STS activity by 23 and 94% when assayed 24 h after administration of the 0.1 and 1 mg/kg doses. E1-STS activity in brain tissue and white blood cells was also found to be inhibited when selected drugs were tested. These studies have identified a number of tricyclic COUMATEs with therapeutic potential.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arylsulfatases / antagonists & inhibitors*
  • Coumarins / chemistry
  • Coumarins / pharmacology*
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Female
  • In Vitro Techniques
  • Liver / drug effects
  • Liver / enzymology
  • Rats
  • Rats, Wistar
  • Steryl-Sulfatase
  • Structure-Activity Relationship

Substances

  • Coumarins
  • Enzyme Inhibitors
  • Arylsulfatases
  • Steryl-Sulfatase