Studies on Aromatase Inhibitors IV. Synthesis and Biological Evaluation of N, N-Disubstituted-5-aminopyrimidine Derivatives

In order to study the potency of the 5-aminopyrimidine skeleton as an aromatase inhibitor, we synthesized various N, N-disubstituted-5-aminopyrimidine derivatives and evaluated their aromatase-inhibitory activity (in vitro) and their inhibitory activity on pregnant mare serum gonadotropin (PMSG)-induced estrogen synthesis (in vivo). Compounds with the fluoro-substituted benzyl group showed potent aromatase inhibition. Among them, 5-[(4-cyanophenyl)(3, 5-difluorobenzyl)amino]pyrimidine (5w, YM553) was a highly potent compound with an IC50 value of 0.038nM for aromatase from human placenta. Its inhibitory effect was approximately four times greater than that of YM511. In addition, YM553 was a weak inhibitor of other enzymes involved in steroid hormone synthesis. These results indicate that YM553, as well as YM511 (a 4-amino-4H-1, 2, 4-triazole derivative), is a promising agent for the treatment of estrogen-dependent diseases.