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Discovery of potent and selective inhibitors of calmodulin-dependent kinase II (CaMKII) |
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| Authors: | Dmitry O Koltun Eric Q Parkhill Rao Kalla Thao D Perry Elfatih Elzein Xiaofen Li Scott P Simonovich Christopher Ziebenhaus Timothy R Hansen Bruno Marchand WaiLok K Hung Leanna Lagpacan Magdeleine Hung Ron G Aoyama Bernard P Murray Jason K Perry John R Somoza Armando G Villaseñor Jeff A Zablocki |
| Institution: | 1. Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, United States;2. Department of Biology, Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, United States;3. Department of Drug Metabolism, Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, United States;4. Department of Structural Chemistry, Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, United States |
| Abstract: | 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. |
| Keywords: | Calmodulin Kinase Calmodulin-dependent kinase CaMKII inhibitor Protein serine/threonine kinase |
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