Guo Zhiqiang, Chen Yongsheng, Wu Dongpei, Zhu Yun-Fei, Struthers R Scott, Saunders John, Xie Qiu, Chen Chen
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 10555 Science Center Drive, San Diego, CA 92121, USA.
Bioorg Med Chem Lett. 2003 Oct 20;13(20):3617-22. doi: 10.1016/s0960-894x(03)00746-7.
The synthesis and SAR studies of thieno[2,3-d]pyrimidine-2,4-diones as human GnRH receptor antagonists to treat reproductive diseases are discussed. It was found that the 2-(2-pyridyl)ethyl group on the 5-aminomethyl functionality of the core structure was a key feature for good receptor binding activity. SAR study of the 6-(4-aminophenyl) group suggests that hydrophobic substituents were preferred. The best compound from this series had binding affinity (K(i)) of 0.4 nM to the human GnRH receptor.
讨论了作为治疗生殖疾病的人促性腺激素释放激素（GnRH）受体拮抗剂的噻吩并[2,3-d]嘧啶-2,4-二酮的合成及构效关系（SAR）研究。发现核心结构5-氨基甲基官能团上的2-（2-吡啶基）乙基是良好受体结合活性的关键特征。对6-（4-氨基苯基）基团的构效关系研究表明，疏水取代基是优选的。该系列中最佳化合物与人GnRH受体的结合亲和力（K(i)）为0.4 nM。
