2,4-二氨基噻唑类化合物作为 Cdk5/p25 激酶抑制剂的构效关系研究。
Structure-activity relationship study of 2,4-diaminothiazoles as Cdk5/p25 kinase inhibitors.
机构信息
Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham & Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA.
出版信息
Bioorg Med Chem Lett. 2011 Apr 1;21(7):2098-101. doi: 10.1016/j.bmcl.2011.01.140. Epub 2011 Feb 3.
Abstract
Cdk5/p25 has emerged as a principle therapeutic target for numerous acute and chronic neurodegenerative diseases, including Alzheimer's disease. A structure-activity relationship study of 2,4-diaminothiazole inhibitors revealed that increased Cdk5/p25 inhibitory activity could be accomplished by incorporating pyridines on the 2-amino group and addition of substituents to the 2- or 3-position of the phenyl ketone moiety. Interpretation of the SAR results for many of the analogs was aided through in silico docking with Cdk5/p25 and calculating protein hydrations sites using WaterMap. Finally, improved in vitro mouse microsomal stability was also achieved.
摘要
Cdk5/p25 已成为许多急性和慢性神经退行性疾病（包括阿尔茨海默病）的主要治疗靶点。对 2,4-二氨基噻唑抑制剂的构效关系研究表明，通过在 2-氨基上引入吡啶环并在苯甲酮部分的 2-或 3-位添加取代基，可以提高 Cdk5/p25 的抑制活性。通过与 Cdk5/p25 的计算机对接，并使用 WaterMap 计算蛋白质水合位点，对许多类似物的 SAR 结果进行了解释。最后，还提高了体外小鼠微粒体稳定性。
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