LY-266111

Partially reduced benzo[f]quinolin-3(4H)-ones are a novel class of potent and selective inhibitors of human type I steroid 5α-reductase (I).Conversion of a variety of 2-tetralones to the corresponding pyrrolidine enamines and condensation with acrylamide afforded the 1,2,5,6-tetrahydrobenzo[f]quinolin-3(4H)-ones.Methylation on N under standard conditions followed by reduction with triethylsilane provided mixtures of the 2 ring juncture isomeric 4-methyl-1,2,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(4H)-ones favoring the trans isomers.Formation of the angular Me compounds, the 10b,4-dimethyl-1,2,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(4H)-ones, utilized the same synthetic strategy beginning with the 1-methyl-2-tetralones.The compounds were evaluated for their ability to inhibit type I I in cultured Hs68 human foreskin fibroblast cells.Compound I (LY 191704), which possessed the optimal N-Me, trans, angular H arrangement, was an extremely potent inhibitor of human type I I with an IC₅₀ of 8 nM.In contrast, the benzoquinolinones, as a class, were weak inhibitors of prostate gland-derived human type II I and of the rat I.