Imidazo[4,5-b]pyridine Derivatives As Inhibitors of Aurora Kinases: Lead Optimization Studies toward the Identification of an Orally Bioavailable Preclinical Development Candidates
Imidazo[4,5-b]pyridine Derivatives As Inhibitors of Aurora Kinases: Lead Optimization Studies toward the Identification of an Orally Bioavailable Preclinical Development Candidates
复制标题
DOI：
10.1021/jm100262j
复制
发表时间：
2010-07-22
影响因子：
7.3
通讯作者：
McDonald, Edward
中科院分区：
文献类型：
--
作者：
Bavetsias, Vassilios;Large, Jonathan M.;McDonald, Edward
使用7作为起始点的先导优化研究导致一类新的基于咪唑并[4，5-B]吡啶的Aurora激酶抑制剂，其在7位具有1-苄基哌嗪基基序，并显示出有利的体外性质。Aurora-A与40 c（CCT 137444）的共沉淀为这类新型抑制剂与Aurora激酶的相互作用提供了清晰的理解。随后通过引入增溶基团的物理化学性质改进导致了3-（（4-（6-溴-2-（4-（4-甲基哌嗪-1-基）苯基）-3H-咪唑并[4，5-B]吡啶-7-基）-哌嗪-1-基）甲基）-5-甲基异恶唑（51，CCT 137690），其是Aurora激酶的有效抑制剂（Aurora-A IC 50 = 0.015 +/-0.003 μ M，Aurora-B IC 50 = 0.025 μ M，Aurora-C IC 50 = 0.019 μ M）。化合物51是高度口服生物可利用的，并且在体内功效研究中，其在口服给药后抑制SW 620结肠癌异种移植物的生长，而没有观察到如由体重减轻定义的毒性。
Lead optimization studies using 7 as the starting point led to a new class of imidazo[4,5-b]pyridine-based inhibitors of Aurora kinases that possessed the 1-benzylpiperazinyl motif at the 7-position, and displayed favorable in vitro properties. Cocrystallization of Aurora-A with 40c (CCT137444) provided a clear understanding into the interactions of this novel class of inhibitors with the Aurora kinases. Subsequent physicochemical property refinement by the incorporation of solubilizing groups led to the identification of 3-((4-(6-bromo-2-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-piperazin-1-yl)methyl)-5-methylisoxazole (51, CCT137690) which is a potent inhibitor of Aurora kinases (Aurora-A IC50 = 0.015 +/- 0.003 mu M, Aurora-B IC50 = 0.025 mu M, Aurora-C IC50 = 0.019 mu M). Compound 51 is highly orally bioavailable, and in in vivo efficacy studies it inhibited the growth of SW620 colon carcinoma xenografts following oral administration with no observed toxicities as defined by body weight loss.