Evaluation of 4′-substituted bicyclic pyridones as non-steroidal inhibitors of steroid 5α-reductase

4′-Substituted bicyclic pyridones were prepared and evaluated as non-steroidal inhibitors of type 1 and 2 steroid 5α-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.

4′-Substituted bicyclic pyridones were prepared and evaluated for non-steroidal inhibition of type 1 and 2 steroid 5α-reductase (SR). SAR for 4′-substituents were determined and compared to SAR derived from a known class of SR inhibitor.Figure optionsDownload as PowerPoint slide