2-(1-adamantyl)-4-(thio)chromenone-6-carboxylic acids: potent reversible inhibitors of human steroid sulfatase.
Steroid sulfatase (STS) is an attractive target for the potential therapy of a number of estrogen- and androgen-dependent disorders. Most potent STS inhibitors known so far act as irreversible enzyme blockers and feature an aryl sulfamate moiety; even minor modifications at the sulfamate group result in drastically decreased activity. On the basis of a recently reported subclass of highly potent STS inhibitors, i.e., chromenone sulfamates, we now extended the investigation of structure-activity relationships to hitherto unstudied sulfamate replacements. Thereby, we discovered 2-(1-adamantyl)-4-(thio)chromenone-6-carboxylic acids (5d and 5j) as potent, reversible inhibitors of STS. In a cell-free system using purified human STS, both new inhibitors show similar Ki values (0.50 microM and 0.53 microM, respectively). However, the thio analogue 5j is superior to 5d (IC50 = 0.18 microM versus 9.4 microM) in a cellular assay system using CHO cells overexpressing STS. Compound 5j is an example of a reversible STS inhibitor with potent activity toward the target enzyme in a cellular test system. Moreover, 5d,j are stable and have no estrogenic potential.
Novartis Institute for Biomedical Research Vienna, Brunnerstrasse 59, A-1235 Vienna, Austria. amarylla.horvath@pharma.novartis.com
Amarylla
A
Horvath
Peter
P
Nussbaumer
Barbara
B
Wolff
Andreas
A
Billich
D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000494:pharmacology; D016466:CHO Cells; D002474:Cell-Free System; D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006224:Cricetinae; D004355:Drug Stability; D006801:Humans; D012996:Solutions; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014867:Water
C488792:2-adamantan-1-yl-4-oxo-4H-thiochromene-6-carboxylic acid; D001578:Benzopyrans; D002867:Chromones; D012996:Solutions; C488791:adamantan-1-yl-4-oxo-4H-chromene-6-carboxylic acid; D014867:Water; D043266:Steryl-Sulfatase; D000218:Adamantane