title: N-substituted 4-(4-carboxyphenoxy)benzamides. Synthesis and evaluation as inhibitors of steroid-5alpha-reductase type 1 and 2.
abstract: In search of non-steroidal inhibitors of human prostatic 5alpha-reductase, we recently described N-substituted 4'-biphenyl-4-carboxylic acids. Here, we report the optimisation of this series of compounds by increasing the conformational flexibility using an ether linker between the steroidal A-C ring mimetics. Ten new compounds were synthesised and tested against human and rat isozymes 1 and 2. The substances showed a broad range of activity from 36% inhibition at a concentration of 10 microM to an IC50 value of 60 nM for compounds 22 and 29 respectively. The most potent compound 26 showed an IC50 value improved by a factor of 5 from 1.9 microM to 0.38 microM in comparison with the parent biphenyl compound 15.
authors.affiliation: 8.5 Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany.
authors.forename: Franck
authors.initials: F
authors.lastname: Picard
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D058891:5-alpha Reductase Inhibitors; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008968:Molecular Conformation; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D058891:5-alpha Reductase Inhibitors; D001549:Benzamides; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C476566:steroid-5alpha-reductase type 1; C476567:steroid-5alpha-reductase type 2