Synthesis of 8-chloro-benzo[c]quinolizin-3-ones as potent and selective inhibitors of human steroid 5alpha-reductase 1

Bioorg Med Chem Lett. 2000 Feb 21;10(4):353-6. doi: 10.1016/s0960-894x(99)00698-8.

Abstract

The synthesis of a series of differently substituted 8-chloro-benzo[c]quinolizin-3-ones, as potent and selective human steroid 5alpha-reductase type 1 inhibitors, has been accomplished by a four-step procedure based on the TiCl4-promoted tandem Mannich-Michael cyclization of 2-silyloxy-1,3-butadienes with N-t-Boc iminium ions from quinolin-2-ones. The presence on the benzo[c]quinolizinone nucleus of a methyl group and a double bond at positions 6 and 4-4a, respectively, as in compound 1d, gave rise to one of the most potent non-steroidal 5alphaR-1 inhibitors reported so far (IC50 = 14 nM).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase / metabolism
  • 5-alpha Reductase Inhibitors*
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Quinolizines / chemical synthesis
  • Quinolizines / chemistry*
  • Quinolizines / pharmacology*
  • Quinolones / chemistry
  • Quinolones / pharmacology
  • Sensitivity and Specificity
  • Structure-Activity Relationship
  • Titanium / metabolism

Substances

  • 5-alpha Reductase Inhibitors
  • Anti-Inflammatory Agents, Non-Steroidal
  • Enzyme Inhibitors
  • Quinolizines
  • Quinolones
  • 8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo(f)quinolin-3(2H)-one
  • titanium tetrachloride
  • Titanium
  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase