Tan Qiang, Blizzard Timothy A, Morgan Jerry D, Birzin Elizabeth T, Chan Wanda, Yang Yi Tien, Pai Lee-Yuh, Hayes Edward C, DaSilva Carolyn A, Warrier Sudha, Yudkovitz Joel, Wilkinson Hilary A, Sharma Nandini, Fitzgerald Paula M D, Li Susan, Colwell Lawrence, Fisher John E, Adamski Sharon, Reszka Alfred A, Kimmel Donald, DiNinno Frank, Rohrer Susan P, Freedman Leonard P, Schaeffer James M, Hammond Milton L
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, RY800-B107, Rahway, NJ 07065, USA.
Bioorg Med Chem Lett. 2005 Mar 15;15(6):1675-81. doi: 10.1016/j.bmcl.2005.01.046.
The discovery, synthesis, and SAR of chromanes as ER alpha subtype selective ligands are described. X-ray studies revealed that the origin of the ER alpha-selectivity resulted from a C-4 trans methyl substitution to the cis-2,3-diphenyl-chromane platform. Selected compounds from this class demonstrated very potent in vivo antagonism of estradiol in an immature rat uterine weight assay, effectively inhibited ovariectomy-induced bone resorption in a 42 days treatment paradigm, and lowered serum cholesterol levels in ovx'd adult rat models. The best antagonists 8F and 12F also exhibited potent inhibition of MCF-7 cell growth and were shown to be estrogen receptor down-regulators (SERDs).
本文描述了作为雌激素受体α亚型选择性配体的色满类化合物的发现、合成及其构效关系。X射线研究表明，雌激素受体α选择性的来源是顺式-2,3-二苯基色满平台的C-4位反式甲基取代。从该类化合物中筛选出的部分化合物在未成熟大鼠子宫重量试验中表现出对雌二醇非常有效的体内拮抗作用，在42天的治疗模式中有效抑制去卵巢诱导的骨吸收，并降低去卵巢成年大鼠模型的血清胆固醇水平。最佳拮抗剂8F和12F还表现出对MCF-7细胞生长的有效抑制作用，并被证明是雌激素受体下调剂（SERD）。
