Efforts to develop a novel class of nonsteroidal
aromatase inhibitors began with the discovery that the
infertility in male rats exposed to high levels of the agricultural fungicide,
fenarimol (alpha-(2-chlorophenyl)-alpha-(4-chlorophenyl)-5-pyrimidine-methanol), was attributable to the inhibition of
aromatase activity within the central nervous system during the critical neonatal period. Although
fenarimol was not particularly potent in inhibiting rat ovarian microsome
aromatase activity in vitro (50% inhibition (IC50) = 4.1 microM). Subsequent testing of a number of analogues led to the identification of
LY56110 (alpha,alpha-bis(4-chlorophenyl)-5-methylpyrimidine) which exhibited an IC50 of 29 nM.
LY56110 was orally active, blocking the
testosterone-induced increase of uterine weight and ovarian
estrogen biosynthesis in immature female rats. In rats with established DMBA-induced mammary
carcinoma, complete
tumor regression was observed in 80% of the animals. Development of
LY56110 was, however, stopped because of its effects on hepatic microsomal
enzymes and an unacceptably long half-life. Structural modifications resulted in the development of the indenopyrimidines. LY113174 (8-chloro-5-(4-chlorophenyl)-5H-indeno less than 1, 2D greater than
pyrimidine) was highly effective in vitro (IC50 = 24 nM) and in vivo but was far less potent than
LY56110 with respect to induction of hepatic microsomal
enzymes. LY113174 exhibited an acceptable
biological half-life and had no effect on
cholesterol side-chain cleavage. The indenopyrimidines appear to be a novel class of nonsteroidal
aromatase inhibitors which may prove useful in the treatment of
estrogen-dependent diseases.