David Ernest Lawhorn

Synthesis of the individual enantiomers of the benzoquinolinone human type 1 steroid 5-α-reductase inhibitors LY191704 and LY266111

Abstract The first syntheses of the individual enantiomers of the benzoquinolinone class of selective inhibitors of human Type 1 steroid 5-α-reductase are described. For benzoquinolinones lacking an angular substituent, the approach relies upon an enamine acryloyl chloride cyclization followed by non-stereoselective reduction and diastereomer separation. Absolute configuration was established by single crystal x-ray diffraction analysis. The angularly methylated benzoquinolinones are prepared in an enantiospecific (deracemizing) fashion from 1-methyl-6-chloro-2-tetralone in 5 steps, employing a “formal 3 + 3 aza-annulation” sequence, with (R) or (S) α-phenethylamine as the source of chirality.

QSAR study of benzoquinolinones as inhibitors of human type 1 5-α-reductase.

Abstract QSAR models have been developed with regression analysis that related a specific lipophilic feature of the substituent of the molecule with biological activity. A second important feature of the compounds, the energy of the HOMO, was revealed using a simple visualization technique.