Synthesis and evaluation of indenopyrazoles as cyclin-dependent kinase inhibitors. 3. Structure activity relationships at C3
Synthesis and evaluation of indenopyrazoles as cyclin-dependent kinase inhibitors. 3. Structure activity relationships at C3
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DOI：
10.1021/jm0201722
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发表时间：
2002-10
影响因子：
7.3
通讯作者：
E. Yue;C. Higley;Dimeo Susan;D. Carini;D. Nugiel;Carrie Benware;P. Benfield;C. Burton;S. Cox;R. Grafstrom;Diane M. Sharp;Lisa M Sisk;J. Boylan;J. Muckelbauer;A. Smallwood;Haiying Chen;Chong-Hwan Chang;S. P. Seitz;G. Trainor
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文献类型：
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作者：
E. Yue;C. Higley;Dimeo Susan;D. Carini;D. Nugiel;Carrie Benware;P. Benfield;C. Burton;S. Cox;R. Grafstrom;Diane M. Sharp;Lisa M Sisk;J. Boylan;J. Muckelbauer;A. Smallwood;Haiying Chen;Chong-Hwan Chang;S. P. Seitz;G. Trainor
茚并[1，2-c]吡唑-4-酮作为细胞周期蛋白依赖性激酶（CDK）抑制剂的发现，导致了一系列新的和有效的化合物的发现。在这里，我们报告的影响取代茚并[1，2-c]吡唑-4-酮核心的C3与烷基，杂环，和取代的苯基。在C3苯环的帕拉取代通常耐受良好;然而，较大的基团通常无活性。对于直接连接到C3的烷基，不容许较长链的取代基;然而，较短的烷基和环状烷基是可接受的。一般而言，C3处的杂环得到最有效的类似物。详细检查了一种这样的杂环24 j，并确定其具有与CDK抑制一致的生物学特性。测定了与CDK 2复合的烷基化合物之一13 q的X射线晶体结构，并显示抑制剂位于酶的腺苷5 '-三磷酸口袋中。
The identification of indeno[1,2-c]pyrazol-4-ones as inhibitors of cyclin-dependent kinases (CDKs) has led to the discovery of a series of novel and potent compounds. Herein, we report the effects of substitutions at C3 of the indeno[1,2-c]pyrazol-4-one core with alkyls, heterocycles, and substituted phenyls. Substitutions at the para position of the phenyl ring at C3 were generally well-tolerated; however, larger groups were generally inactive. For alkyls directly attached to C3, longer chain substituents were not tolerated; however, shorter alkyl groups and cyclic alkyls were acceptable. In general, the heterocycles at C3 gave the most potent analogues. One such heterocycle, 24j, was examined in detail and was determined to have a biological profile consistent with CDK inhibition. An X-ray crystal structure of one of the alkyl compounds, 13q, complexed with CDK2 was determined and showed the inhibitor residing in the adenosine 5'-triphosphate pocket of the enzyme.