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

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.

• Authors: 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
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 26 Issue 17 Pg. 4362-6 (09 01 2016) ISSN: 1464-3405 [Electronic] England
• PMID: 27491711 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

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

Topics

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