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

doi:10.1016/j.bmcl.2017.10.040

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

Bioorg Med Chem Lett. 2018 Feb 1;28(3):541-546. doi: 10.1016/j.bmcl.2017.10.040. Epub 2017 Oct 20.

Authors

Dmitry O Koltun¹, Eric Q Parkhill², Rao Kalla², Thao D Perry², Elfatih Elzein², Xiaofen Li², Scott P Simonovich², Christopher Ziebenhaus², Timothy R Hansen², Bruno Marchand³, WaiLok K Hung³, Leanna Lagpacan³, Magdeleine Hung³, Ron G Aoyama⁴, Bernard P Murray⁴, Jason K Perry⁵, John R Somoza⁵, Armando G Villaseñor⁵, Nikos Pagratis³, Jeff A Zablocki²

Affiliations

¹ Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, United States. Electronic address: dmitry.koltun@gilead.com.
² Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, United States.
³ Department of Biology, Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, United States.
⁴ Department of Drug Metabolism, Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, United States.
⁵ Department of Structural Chemistry, Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, United States.

PMID: 29254643
DOI: 10.1016/j.bmcl.2017.10.040

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: CaMKII inhibitor; Calmodulin; Calmodulin-dependent kinase; Kinase; Protein serine/threonine kinase.

MeSH terms

Calcium-Calmodulin-Dependent Protein Kinase Type 2 / antagonists & inhibitors*
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
Calcium-Calmodulin-Dependent Protein Kinase Type 2