设计蛋白激酶 A 为结构替代物的 Rho 激酶 1 和 2 的氨苯并噻唑抑制剂。
Design of Aminobenzothiazole Inhibitors of Rho Kinases 1 and 2 by Using Protein Kinase A as a Structure Surrogate.
机构信息
AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA, 01605, USA.
出版信息
Chembiochem. 2018 Mar 16;19(6):613-621. doi: 10.1002/cbic.201700547. Epub 2018 Jan 30.
We describe the design, synthesis, and structure-activity relationships (SARs) of a series of 2-aminobenzothiazole inhibitors of Rho kinases (ROCKs) 1 and 2, which were optimized to low nanomolar potencies by use of protein kinase A (PKA) as a structure surrogate to guide compound design. A subset of these molecules also showed robust activity in a cell-based myosin phosphatase assay and in a mechanical hyperalgesia in vivo pain model.
我们描述了一系列 2-氨基苯并噻唑 Rho 激酶（ROCK）1 和 2 抑制剂的设计、合成和构效关系（SARs），这些抑制剂通过使用蛋白激酶 A（PKA）作为结构替代物来指导化合物设计，优化后具有低纳摩尔的效力。这些分子中的一部分在基于细胞的肌球蛋白磷酸酶测定和体内机械性痛觉过敏疼痛模型中也表现出很强的活性。
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