title: 2-Substituted 4-(thio)chromenone 6-O-sulfamates: potent inhibitors of human steroid sulfatase.
abstract: Steroid sulfatase (STS) has emerged as a highly attractive target for the therapy of a number of disorders. Starting with the known inhibitor estrone sulfamate (1) as lead compound and with the finding that steroid sulfamates containing a nonaromatic A-ring are inactive, chromen-4-one sulfamates were designed, prepared, and tested for their ability to block human STS. This new class of nonsteroidal inhibitors shows high potency when the sulfamate group and the side chain are situated in diagonally opposite positions (i.e., 2,6- and 3,7-substitution pattern). The highest activity is achieved with fully branched, bulky aliphatic side chains and with thiochromen-4-one as the core element. 2-(1-Adamantyl)-4H-thiochromen-4-on-6-O-sulfamate (6c) is the most potent STS inhibitor discovered so far, and it is about 170-fold superior to 1. As with 1, all chromenone sulfamates are irreversible inhibitors of STS with a biphasic time course of inactivation.
authors.affiliation: Novartis Research Institute Vienna, Brunnerstrasse 59, A-1235 Vienna, Austria. peter.nussbaumer@pharma.novartis.com
authors.forename: Peter
authors.initials: P
authors.lastname: Nussbaumer
authors.forename: Philipp
authors.initials: P
authors.lastname: Lehr
authors.forename: Andreas
authors.initials: A
authors.lastname: Billich
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001192:Arylsulfatases / Q000037:antagonists & inhibitors*; D016466:CHO Cells; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D007700:Kinetics; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D010920:Placenta / Q000648:ultrastructure; D043266:Steryl-Sulfatase; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C465777:2-(1-adamantyl)-4H-thiochromen-4-on-6-O-sulfamate; D004791:Enzyme Inhibitors; D013451:Sulfonic Acids; D001192:Arylsulfatases; D043266:Steryl-Sulfatase; D000218:Adamantane