title: Synthesis of 3-spiromorpholinone androsterone derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase type 3.
abstract: Spiromorpholinone derivatives were synthesized from androsterone or cyclohexanone in 6 or 3 steps, respectively, and these scaffolds were used for the introduction of a hydrophobic group via a nucleophilic substitution. Non-steroidal spiromorpholinones are not active as inhibitors of 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3), but steroidal morpholinones are very potent inhibitors. In fact, those with (S) stereochemistry are more active than their (R) homologues, whereas N-benzylated compounds are more active than their non substituted precursors. The target compounds exhibited strong inhibition of 17β-HSD3 in rat testis homogenate (87-92% inhibition at 1 μM).
authors.affiliation: Laboratory of Medicinal Chemistry, CHU de Québec - Research Center (CHUL, T4), Québec, Qc, Canada; Department of Molecular Medicine, Faculty of Medicine, Laval University, Québec, Qc, Canada.
authors.forename: Guy Bertrand
authors.initials: GB
authors.lastname: Djigoué
authors.forename: Lucie Carolle
authors.initials: LC
authors.lastname: Kenmogne
authors.forename: Jenny
authors.initials: J
authors.lastname: Roy
authors.forename: Donald
authors.initials: D
authors.lastname: Poirier
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000738:Androsterone / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D008297:Male; D051381:Rats; D013329:Structure-Activity Relationship; D013737:Testis / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D000738:Androsterone; D015067:17-Hydroxysteroid Dehydrogenases; C476565:17beta-hydroxysteroid dehydrogenase type 3
keywords: 17β-Hydroxysteroid dehydrogenase; Enzyme inhibitor; Spiromorpholinone; Steroids; Synthesis