Discovery of potent and selective inhibitors of calmodulin-dependent kinase II (CaMKII).

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,Nikos Pagratis,Jeff A Zablocki

Bioorganic & Medicinal Chemistry Letters（2018）

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摘要

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.

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关键词

Calmodulin,Kinase,Calmodulin-dependent kinase,CaMKII inhibitor,Protein serine/threonine kinase

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