title: Evaluation of 4'-substituted bicyclic pyridones as non-steroidal inhibitors of steroid 5alpha-reductase.
abstract: 4'-Substituted bicyclic pyridones were prepared and evaluated as non-steroidal inhibitors of type 1 and 2 steroid 5alpha-reductase (SR). A range of 4'-substituents were incorporated into the bicyclic scaffold to investigate SAR within and across different classes of non-steroidal inhibitors of SR. Bicyclic pyridones containing a 4'-benzoyl or long carbon chain tether showed more potent inhibition against type 1 SR than inhibitors with N-substituted acetamide groups in the 4'-position. SAR derived from 4'-substituted bicyclic pyridones reported here do not correlate with SAR derived from known potent 4'-substituted biaryl acid SR inhibitors. A 4'-benzoyl group is favoured by the active site in both isozymes.
authors.affiliation: Department of Chemistry, University of Canterbury, Private Bag 4800, Christchurch 8020, New Zealand. am160@st-andrews.ac.uk <am160@st-andrews.ac.uk>
authors.forename: Anna R
authors.initials: AR
authors.lastname: McCarthy
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Abell
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D058891:5-alpha Reductase Inhibitors; D001665:Binding Sites; D002244:Carbon / Q000737:chemistry; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000166:cytology; D008956:Models, Chemical; D020033:Protein Isoforms; D011728:Pyridones / Q000737:chemistry*; D013256:Steroids / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D058891:5-alpha Reductase Inhibitors; D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D011728:Pyridones; D013256:Steroids; D002244:Carbon; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C476566:steroid-5alpha-reductase type 1