Boga Sobhana Babu, Alhassan Abdul-Basit, Liu Jian, Guiadeen Deodial, Krikorian Arto, Gao Xiaolei, Wang James, Yu Younong, Anand Rajan, Liu Shilan, Yang Chundao, Wu Hao, Cai Jiaqiang, Zhu Hugh, Desai Jagdish, Maloney Kevin, Gao Ying-Duo, Fischmann Thierry O, Presland Jeremy, Mansueto My, Xu Zangwei, Leccese Erica, Knemeyer Ian, Garlisi Charles G, Bays Nathan, Stivers Peter, Brandish Philip E, Hicks Alexandra, Cooper Alan, Kim Ronald M, Kozlowski Joseph A
Department of Early Development and Discovery Sciences, MRL, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
Department of Early Development and Discovery Sciences, MRL, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
Bioorg Med Chem Lett. 2017 Aug 15;27(16):3939-3943. doi: 10.1016/j.bmcl.2017.03.040. Epub 2017 Mar 18.
8-Amino-imidazo[1,5-a]pyrazine-based Bruton's tyrosine kinase (BTK) inhibitors, such as 6, exhibited potent inhibition of BTK but required improvements in both kinase and hERG selectivity (Liu et al., 2016; Gao et al., 2017). In an effort to maintain the inhibitory activity of these analogs and improve their selectivity profiles, we carried out SAR exploration of groups at the 3-position of pyrazine compound 6. This effort led to the discovery of the morpholine group as an optimized pharmacophore. Compounds 13, 23 and 38 displayed excellent BTK potencies, kinase and hERG selectivities, and pharmacokinetic profiles.
基于8-氨基咪唑并[1,5-a]吡嗪的布鲁顿酪氨酸激酶（BTK）抑制剂，如化合物6，对BTK表现出强效抑制作用，但在激酶和人醚-去极化相关基因（hERG）选择性方面仍需改进（Liu等人，2016年；Gao等人，2017年）。为了维持这些类似物的抑制活性并改善其选择性，我们对吡嗪化合物6的3-位基团进行了构效关系（SAR）探索。这项工作导致发现吗啉基团是一种优化的药效团。化合物13、23和38表现出优异的BTK活性、激酶和hERG选择性以及药代动力学特征。
