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Bioorg Med Chem Lett. 2014 Mar 15;24(6):1466-71. doi: 10.1016/j.bmcl.2014.02.011. Epub 2014 Feb 15.

The discovery of reverse tricyclic pyridone JAK2 inhibitors. Part 2: lead optimization.

Author information

  • 1Department of Medicinal Chemistry, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: tony_siu@merck.com.
  • 2Department of Medicinal Chemistry, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • 3Department of Structural Chemistry, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • 4Department of In Vitro Sciences, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • 5Department of Pharmacology, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • 6Department of Drug Metabolism, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • 7Department of Basic Pharmaceutical Sciences, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • 8Department of Oncology, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.

Abstract

This communication discusses the discovery of novel reverse tricyclic pyridones as inhibitors of Janus kinase 2 (JAK2). By using a kinase cross screening approach coupled with molecular modeling, a unique inhibitor-water interaction was discovered to impart excellent broad kinase selectivity. Improvements in intrinsic potency were achieved by utilizing a rapid library approach, while targeted structural changes to lower lipophilicity led to improved rat pharmacokinetics. This multi-pronged approach led to the identification of 31, which demonstrated encouraging rat pharmacokinetics, in vivo potency, and excellent off-target kinase selectivity.

Copyright © 2014 Elsevier Ltd. All rights reserved.

KEYWORDS:

JAK2; Kinase partition index; Kinase selectivity; Kinases; Ligand binding affinity; Molecular modeling; Water interaction

PMID:
24582987
[PubMed - indexed for MEDLINE]
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