Structure guided design of a series of selective pyrrolopyrimidinone MARK inhibitors

Jason D Katz; Andrew Haidle; Kaleen K Childers; Anna A Zabierek; James P Jewell; Yongquan Hou; Michael D Altman; Alexander Szewczak; Dapeng Chen; Andreas Harsch; Mansuo Hayashi; Lee Warren; Michael Hutton; Hugh Nuthall; Hua-Poo Su; Sanjeev Munshi; Matt G Stanton; Ian W Davies; Ben Munoz; Alan Northrup

doi:10.1016/j.bmcl.2016.08.068

Structure guided design of a series of selective pyrrolopyrimidinone MARK inhibitors

Bioorg Med Chem Lett. 2017 Jan 1;27(1):114-120. doi: 10.1016/j.bmcl.2016.08.068. Epub 2016 Oct 22.

Authors

Jason D Katz¹, Andrew Haidle², Kaleen K Childers², Anna A Zabierek², James P Jewell², Yongquan Hou², Michael D Altman³, Alexander Szewczak⁴, Dapeng Chen⁵, Andreas Harsch⁵, Mansuo Hayashi⁶, Lee Warren⁶, Michael Hutton⁶, Hugh Nuthall⁶, Hua-Poo Su⁷, Sanjeev Munshi⁷, Matt G Stanton², Ian W Davies², Ben Munoz², Alan Northrup²

Affiliations

¹ Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: [email protected].
² Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
³ Department of Structural Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
⁴ Department of In Vitro Sciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
⁵ Department of Drug Metabolism, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
⁶ Department of Neuroscience, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
⁷ Department of Structural Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.

PMID: 27816515
DOI: 10.1016/j.bmcl.2016.08.068

Abstract

The initial structure activity relationships around an isoindoline uHTS hit will be described. Information gleaned from ligand co-crystal structures allowed for rapid refinements in both MARK potency and kinase selectivity. These efforts allowed for the identification of a compound with properties suitable for use as an in vitro tool compound for validation studies on MARK as a viable target for Alzheimer's disease.

Keywords: Alzheimer’s disease; Kinase; MARK; Pyrrolopyrimidinone; Tau.

MeSH terms

Alzheimer Disease / drug therapy
Alzheimer Disease / metabolism
Cell Line
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Design*
Humans
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / metabolism
Pyrimidinones / chemical synthesis
Pyrimidinones / chemistry
Pyrimidinones / pharmacology*
Pyrroles / chemical synthesis
Pyrroles / chemistry
Pyrroles / pharmacology*
Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
Pyrimidinones
Pyrroles
MARK1 protein, human
MARK2 protein, human
MARK3 protein, human
MARK4 protein, human
Protein Serine-Threonine Kinases