Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part IV: Preliminary control of αvβ3 selectivity by meta-oriented substitution
Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part IV: Preliminary control of αvβ3 selectivity by meta-oriented substitution
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基于三环药效基团的分子作为新型整合素 αvβ3 拮抗剂，第四部分：通过元定向取代初步控制 αvβ3 选择性。
DOI：
10.1016/j.bmc.2006.01.062
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发表时间：
2006
影响因子：
3.5
通讯作者：
K. Ajito
中科院分区：
文献类型：
--
作者：
Dai Kubota;M. Ishikawa;M. Ishikawa;N. Yahata;Shoichi Murakami;K. Fujishima;M. Kitakaze;K. Ajito
为了确定具有三环药效团的αvβ3/αIIbβ 3双重拮抗剂的体内效力，需要相应的αvβ3选择性拮抗剂作为对照。我们最初采用了两种合成方法来获得基于RGD识别模式或基于中心苯环与相邻杂环之间的二面角的修饰的αvβ3选择性拮抗剂，但都被证明是不成功的。然而，在具有三环药效团的化合物家族中，首次合成了中心苯环间位取代的新型拮抗剂，对αvβ 3的选择性弱于αIIbβ 3。优化后的后向拮抗剂提供了一种αvβ3选择性拮抗剂，不仅在受体结合试验中，而且在细胞粘附试验中显示出抑制活性。
To establish the in vivo efficacy of αvβ3/αIIbβ3dual antagonists possessing a tricyclic pharmacophore, a corresponding αvβ3-selective antagonist was required as a control. We initially took two synthetic approaches to obtain αvβ3-selective antagonists based on the RGD recognition pattern or on modification of the dihedral angle between the central benzene ring and the adjacent heterocycle, but both proved unsuccessful. However, synthesis of novel antagonists with meta-substitution of the central benzene ring generated weak selectivity for αvβ3over αIIbβ3for the first time in the family of compounds with the tricyclic pharmacophore. Optimization of meta-oriented antagonists furnished an αvβ3-selective antagonist exhibiting inhibitory activity not only in a receptor-binding assay, but also in a cell adhesion assay.
有效且选择性的拟肽抑制剂在糖蛋白 IIb-IIIa 中诱导可逆构象变化。
影响因子：
20.3
作者：
Kouns,WC;Kirchhofer,D;Hadváry,P;Edenhofer,A;Weller,T;Pfenninger,G;Baumgartner,HR;Jennings,LK;Steiner,B
通讯作者：
Steiner,B
影响因子：
20.1
作者：
LIAW, L;ALMEIDA, M;GIACHELLI, CM
通讯作者：
GIACHELLI, CM