Yonetoku Yasuhiro, Kubota Hirokazu, Okamoto Yoshinori, Ishikawa Jun, Takeuchi Makoto, Ohta Mitsuaki, Tsukamoto Shin-ichi
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Bioorg Med Chem. 2006 Aug 1;14(15):5370-83. doi: 10.1016/j.bmc.2006.03.039. Epub 2006 Apr 17.
To identify potent and selective calcium-release-activated calcium (CRAC) channel inhibitors, we examined the structure-activity relationships of the pyrazole and thiophene moieties in compound 4. Compound 25b was found to exhibit highly potent and selective inhibitory activity for CRAC channels and further modifications of the pyrazole and benzoyl moieties of compound 25b produced compound 29. These compounds were potent inhibitors of IL-2 production in vitro and also acted as inhibitors in pharmacological models of diseases resulting from T-lymphocyte activation, after oral administration.
为了鉴定强效且选择性的钙释放激活钙（CRAC）通道抑制剂，我们研究了化合物4中吡唑和噻吩部分的构效关系。发现化合物25b对CRAC通道表现出高效且选择性的抑制活性，对化合物25b的吡唑和苯甲酰部分进行进一步修饰得到了化合物29。这些化合物在体外是白细胞介素-2产生的强效抑制剂，口服给药后在由T淋巴细胞激活引起的疾病的药理模型中也起抑制剂作用。
