Design and synthesis of a new class of selective integrin α5β1 antagonists
Design and synthesis of a new class of selective integrin α5β1 antagonists
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DOI：
10.1021/jm070002v
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发表时间：
2007-08-09
影响因子：
7.3
通讯作者：
Zahn, Grit
中科院分区：
文献类型：
--
作者：
Stragies, Roland;Osterkamp, Frank;Zahn, Grit
从与肽配体复合的整合素α v β 3的结构出发，加上非肽配体的SAR数据，我们推导出一类新的整合素α 5 β 1拮抗剂（1）。应用几种合成策略来评估基本药效团基团R-1至R-3周围的化学空间，以获得作为整联蛋白α 5 β 1拮抗剂的高活性和选择性的吡咯烷衍生物。通过将R3的磺酰胺部分转换为均三甲苯酰胺部分来控制整联蛋白选择性。这一发现代表了调节对其他相关整合素受体的选择性的一般特征。基于各种体外研究的令人鼓舞的结果，选择最具活性的化合物用于动物模型和临床前开发的进一步体内研究。
Starting from the structure of integrin alpha v beta 3 in a complex with a peptidic ligand plus SAR data on nonpeptidic ligands, we derived a new class of integrin alpha 5 beta 1 antagonists (1). Several synthesis strategies were applied to evaluate the chemical space around the essential pharmacophore groups R-1 to R-3 to obtain highly active and selective pyrrolidine derivatives as integrin alpha 5 beta 1 antagonists. Integrin selectivity was controlled by switching from a sulfonamide moiety to a mesitylene amide moiety for R3. This finding represents a general feature for modulating selectivity toward other related integrin receptors. On the basis of the encouraging results from various in vitro studies, the most active compounds were selected for further in vivo studies in animal models and preclinical development.