Optimization of microtubule affinity regulating kinase (MARK) inhibitors with improved physical properties. Issue 17 (1st September 2016)

• Record Type: Journal Article
• Authors: Sloman, David L.; Noucti, Njamkou; Altman, Michael D.; Chen, Dapeng; Mislak, Andrea C.; Szewczak, Alexander; Hayashi, Mansuo; Warren, Lee; Dellovade, Tammy; Wu, Zhenhua; Marcus, Jacob; Walker, Deborah; Su, Hua-Poo; Edavettal, Suzanne C.; Munshi, Sanjeev; Hutton, Michael; Nuthall, Hugh; Stanton, Matthew G.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 17(2016)
• Page Start: 4362
• Page End: 4366
• Publication Date: 2016-09-01
• Subjects: AD Alzheimer's disease -- MARK microtubule affinity regulating kinase -- NFTs neurofibrillary tangles -- CSF cerebrospinal fluid -- CYP cytochrome P450 -- Pgp P-glycoprotein -- LE ligand efficiency -- PSA polar surface area; MARK -- Kinase -- Alzheimer's disease -- Amine basicity -- Fluorine; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.02.003
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.