Inhibition of steroid sulphatase activity by tricyclic coumarin sulphamates

The identification of the active pharmacophore: required for potent inhibit ion of steroid sulphatase activity, i.e. an aryl-O-sulphamate structure. ha s led to the synthesis and testing of a large number of 1 . 4 ring-based in hibitors. 4-Methylcoumarin-7-O-sulphamate (COUMATE) was one of the first no n-steroid based inhibitors identified. In an attempt to increase the potenc y of this class of inhibitor a series of tricyclic COURMATEs (665 - 6615 CO URMATEs) have been synthesised and evaluated. Using placental microsomes as a source of oestrone sulphatase (EI-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 a n IC50 of 1 nM. Selected inhibitors were tested for their in vivo potency b y administration of a single close (0.1 or I mg/kg. p.o.) to female rats. S urprisingly, in vivo 6615 COUMATE proved to be the most active drug inhibit ing rat liver EI-STS activity by 23 and 94% when assayed 24 h after adminis tration of the 0.1 and 1 mg/kg doses. EI-STS activity in brain tissue and w hite blood cells was also found to be inhibited when selected drugs were te sted. These studies: have identified a number of tricyclic COUMATEs with th erapeutic potential. (C) 2001 Elsevier Science Ltd. All rights reserved.