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

Structure guided design of a series of selective pyrrolopyrimidinone MARK inhibitors.

Author information

1
Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: jason_katz2@merck.com.
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.

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

PMID:
27816515
DOI:
10.1016/j.bmcl.2016.08.068
[Indexed for MEDLINE]

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