发现钙调蛋白依赖性激酶II（CaMKII）的强效和选择性抑制剂。
Discovery of potent and selective inhibitors of calmodulin-dependent kinase II (CaMKII).
作者信息
Koltun Dmitry O, Parkhill Eric Q, Kalla Rao, Perry Thao D, Elzein Elfatih, Li Xiaofen, Simonovich Scott P, Ziebenhaus Christopher, Hansen Timothy R, Marchand Bruno, Hung WaiLok K, Lagpacan Leanna, Hung Magdeleine, Aoyama Ron G, Murray Bernard P, Perry Jason K, Somoza John R, Villaseñor Armando G, Pagratis Nikos, Zablocki Jeff A
机构信息
Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, United States.
Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, United States.
出版信息
Bioorg Med Chem Lett. 2018 Feb 1;28(3):541-546. doi: 10.1016/j.bmcl.2017.10.040. Epub 2017 Oct 20.
We hereby disclose the discovery of inhibitors of CaMKII (7h and 7i) that are highly potent in rat ventricular myocytes, selective against hERG and other off-target kinases, while possessing good CaMKII tissue isoform selectivity (cardiac γ/δ vs. neuronal α/β). In vitro and in vivo ADME/PK studies demonstrated the suitability of these CaMKII inhibitors for PO (7h rat F = 73%) and IV pharmacological studies.
我们在此披露已发现CaMKII抑制剂（7h和7i），其在大鼠心室肌细胞中具有高效能，对hERG及其他脱靶激酶具有选择性，同时对CaMKII组织亚型具有良好的选择性（心脏γ/δ亚型与神经元α/β亚型）。体外和体内的药物代谢动力学/药物动力学（ADME/PK）研究表明，这些CaMKII抑制剂适用于口服给药（7h在大鼠体内的生物利用度F = 73%）和静脉注射的药理学研究。
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