Discovery of potent and selective inhibitors of calmodulin-dependent kinase II (CaMKII). Issue 3 (1st February 2018)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 3(2018)
• Page Start: 541
• Page End: 546
• Publication Date: 2018-02-01
• Subjects: Calmodulin -- Kinase -- Calmodulin-dependent kinase -- CaMKII inhibitor -- Protein serine/threonine kinase; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.10.040
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: We hereby disclose the discovery of inhibitors of CaMKII (7h and7i ) 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.