2. Academic Validation
  3. Optimization of microtubule affinity regulating kinase (MARK) inhibitors with improved physical properties

Optimization of microtubule affinity regulating kinase (MARK) inhibitors with improved physical properties

  • Bioorg Med Chem Lett. 2016 Sep 1;26(17):4362-6. doi: 10.1016/j.bmcl.2016.02.003.
David L Sloman 1,  Njamkou Noucti 1,  Michael D Altman 2,  Dapeng Chen 3,  Andrea C Mislak 3,  Alexander Szewczak 4,  Mansuo Hayashi 4,  Lee Warren 4,  Tammy Dellovade 5,  Zhenhua Wu 5,  Jacob Marcus 6,  Deborah Walker 7,  Hua-Poo Su 8,  Suzanne C Edavettal 8,  Sanjeev Munshi 8,  Michael Hutton 6,  Hugh Nuthall 6,  Matthew G Stanton 1
Affiliations

Affiliations

  • 1 Discovery Chemistry, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States.
  • 2 Chemistry Modeling and Informatics, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States.
  • 3 Drug Metabolism and Pharmacokinetics, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States.
  • 4 CNS Pharmacology, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States.
  • 5 Core Pharmacology, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States.
  • 6 Neuroscience Drug Discovery, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States.
  • 7 Pharmaceutical Research and Development, Merck and Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02215, United States.
  • 8 Structural Biology, 770 Sumneytown Pike, West Point, PA 19486, United States.
PMID: 27491711 DOI: 10.1016/j.bmcl.2016.02.003
Abstract

Inhibition of microtubule affinity regulating kinase (MARK) represents a potentially attractive means of arresting neurofibrillary tangle pathology in Alzheimer's disease. This manuscript outlines efforts to optimize a pyrazolopyrimidine series of MARK inhibitors by focusing on improvements in potency, physical properties and attributes amenable to CNS penetration. A unique cylcyclohexyldiamine scaffold was identified that led to remarkable improvements in potency, opening up opportunities to reduce MW, Pgp efflux and improve pharmacokinetic properties while also conferring improved solubility.

Keywords

Alzheimer’s disease; Amine basicity; Fluorine; Kinase; MARK.

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