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Title: 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:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1404981
Resource Type:
Journal Article
Resource Relation:
Journal Name: Bioorganic and Medicinal Chemistry Letters; Journal Volume: 26; Journal Issue: 17
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 60 APPLIED LIFE SCIENCES

Citation Formats

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, and Stanton, Matthew G. Optimization of microtubule affinity regulating kinase (MARK) inhibitors with improved physical properties. United States: N. p., 2016. Web. doi:10.1016/j.bmcl.2016.02.003.
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. Optimization of microtubule affinity regulating kinase (MARK) inhibitors with improved physical properties. United States. doi:10.1016/j.bmcl.2016.02.003.
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, and Stanton, Matthew G. Thu . "Optimization of microtubule affinity regulating kinase (MARK) inhibitors with improved physical properties". United States. doi:10.1016/j.bmcl.2016.02.003.
@article{osti_1404981,
title = {Optimization of microtubule affinity regulating kinase (MARK) inhibitors with improved physical properties},
author = {Sloman, David L. and Noucti, Njamkou and Altman, Michael D. and Chen, Dapeng and Mislak, Andrea C. and Szewczak, Alexander and Hayashi, Mansuo and Warren, Lee and Dellovade, Tammy and Wu, Zhenhua and Marcus, Jacob and Walker, Deborah and Su, Hua-Poo and Edavettal, Suzanne C. and Munshi, Sanjeev and Hutton, Michael and Nuthall, Hugh and Stanton, Matthew G.},
abstractNote = {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.},
doi = {10.1016/j.bmcl.2016.02.003},
journal = {Bioorganic and Medicinal Chemistry Letters},
number = 17,
volume = 26,
place = {United States},
year = {Thu Sep 01 00:00:00 EDT 2016},
month = {Thu Sep 01 00:00:00 EDT 2016}
}