Back to Search
Start Over
Optimization of microtubule affinity regulating kinase (MARK) inhibitors with improved physical properties.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2016 Sep 01; Vol. 26 (17), pp. 4362-6. Date of Electronic Publication: 2016 Feb 06. - Publication Year :
- 2016
-
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.<br /> (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Crystallography, X-Ray
Dogs
Enzyme Activation drug effects
Enzyme Inhibitors chemistry
Enzyme Inhibitors pharmacology
Heterocyclic Compounds pharmacology
Humans
Inhibitory Concentration 50
Molecular Weight
Rats
Solubility
Enzyme Inhibitors chemical synthesis
Heterocyclic Compounds chemistry
Protein Serine-Threonine Kinases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 26
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 27491711
- Full Text :
- https://doi.org/10.1016/j.bmcl.2016.02.003