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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 |
| Affiliation: | 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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