title: A 6beta-(thiaheptanamide) derivative of estradiol as inhibitor of 17beta-hydroxysteroid dehydrogenase type 1.
abstract: In an effort to develop potent agents for reducing the levels of the active estrogen, estradiol, we developed a new category of 17beta-hydroxysteroid dehydrogenase (17beta-HSD) type 1 inhibitors. The compounds described possess a butyl methyl alkylamide side chain linked to the C6 position of estradiol by a thioether. With a series of epimeric mixtures, an optimal side-chain length of five methylene groups (between the amide group and steroid part) was first determined. Thereafter, both C6 epimers of optimized mixture were obtained after high-pressure liquid chromatography separation. 1H and 13C NMR experiments were performed to confirm the stereochemistry of each epimer. The 6beta-orientation of the side-chain was found to be crucial for enzymatic inhibition. Indeed, for the optimized side-chain length, the compound with a beta-orientation (5: N-butyl,N-methyl 7-(3',17'beta-dihydroxy-1',3',5'( 10')-estratriene-6'beta-yl)-7-thiaheptanamide) was 70-fold more potent than the 6alpha-analog. Compound 5 did not inactivate 17beta-HSD type 1, suggesting a reversible inhibitor. In addition, it was found to be a more potent inhibitor than the substrate estrone itself or a panel of three known inhibitors.
authors.affiliation: Medicinal Chemistry Division, CHUL Research Center and Laval University, Quebec, Canada. donald.poirier@crchul.ulaval.ca
authors.forename: D
authors.initials: D
authors.lastname: Poirier
authors.forename: P
authors.initials: P
authors.lastname: Dionne
authors.forename: S
authors.initials: S
authors.lastname: Auger
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D045166:Estradiol Congeners / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004970:Estrone / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D045166:Estradiol Congeners; D004965:Estrogen Antagonists; C111847:N-butyl-N-methyl-7-(3',17'beta-dihydroxy-1',3',5'(10')-estratriene-6'beta-yl)-7-thiaheptanamide; D004970:Estrone; D004958:Estradiol; D015067:17-Hydroxysteroid Dehydrogenases