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

David L Sloman; Njamkou Noucti; Michael D Altman; Dapeng Chen; Andrea C Mislak; Alexander Szewczak; Mansuo Hayashi; Lee Warren; Tammy Dellovade; Zhenhua Wu; Jacob Marcus; Deborah Walker; Hua-Poo Su; Suzanne C Edavettal; Sanjeev Munshi; Michael Hutton; Hugh Nuthall; Matthew G Stanton

doi:10.1016/j.bmcl.2016.02.003

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. Epub 2016 Feb 6.

Authors

David L Sloman¹, Njamkou Noucti¹, Michael D Altman², Dapeng Chen³, Andrea C Mislak³, Alexander Szewczak⁴, Mansuo Hayashi⁴, Lee Warren⁴, Tammy Dellovade⁵, Zhenhua Wu⁵, Jacob Marcus⁶, Deborah Walker⁷, Hua-Poo Su⁸, Suzanne C Edavettal⁸, Sanjeev Munshi⁸, Michael Hutton⁶, Hugh Nuthall⁶, Matthew G Stanton¹

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.

MeSH terms

Animals
Crystallography, X-Ray
Dogs
Enzyme Activation / drug effects
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Heterocyclic Compounds / chemistry*
Heterocyclic Compounds / pharmacology
Humans
Inhibitory Concentration 50
Molecular Weight
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Rats
Solubility

Substances

Enzyme Inhibitors
Heterocyclic Compounds
MARK3 protein, human
Protein Serine-Threonine Kinases