Okada M, Yoden T, Kawaminami E, Shimada Y, Kudoh M, Isomura Y
Medicinal Chemistry Research II, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Chem Pharm Bull (Tokyo). 1997 Aug;45(8):1293-9. doi: 10.1248/cpb.45.1293.
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.
为了研究5-氨基嘧啶骨架作为芳香酶抑制剂的效力，我们合成了各种N,N-二取代-5-氨基嘧啶衍生物，并评估了它们的芳香酶抑制活性（体外）以及对孕马血清促性腺激素（PMSG）诱导的雌激素合成的抑制活性（体内）。带有氟取代苄基的化合物表现出强效的芳香酶抑制作用。其中，5-[(4-氰基苯基)(3,5-二氟苄基)氨基]嘧啶（5w，YM553）是一种高效化合物，对人胎盘芳香酶的IC50值为0.038 nM。其抑制作用约为YM511的四倍。此外，YM553是参与类固醇激素合成的其他酶的弱抑制剂。这些结果表明，YM553以及YM511（一种4-氨基-4H-1,2,4-三唑衍生物）是治疗雌激素依赖性疾病的有前景的药物。
