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 0.038 nM 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.