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A Selective and Brain Penetrant p38αMAPK Inhibitor Candidate for Neurologic and Neuropsychiatric Disorders That Attenuates Neuroinflammation and Cognitive Dysfunction
[Image: see text] The p38αMAPK is a serine/threonine protein kinase and a key node in the intracellular signaling networks that transduce and amplify stress signals into physiological changes. A preponderance of preclinical data and clinical observations established p38αMAPK as a brain drug discover...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2019
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580366/ https://www.ncbi.nlm.nih.gov/pubmed/30978288 http://dx.doi.org/10.1021/acs.jmedchem.9b00058 |
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author | Roy, Saktimayee M. Minasov, George Arancio, Ottavio Chico, Laura W. Van Eldik, Linda J. Anderson, Wayne F. Pelletier, Jeffrey C. Watterson, D. Martin |
author_facet | Roy, Saktimayee M. Minasov, George Arancio, Ottavio Chico, Laura W. Van Eldik, Linda J. Anderson, Wayne F. Pelletier, Jeffrey C. Watterson, D. Martin |
author_sort | Roy, Saktimayee M. |
collection | PubMed |
description | [Image: see text] The p38αMAPK is a serine/threonine protein kinase and a key node in the intracellular signaling networks that transduce and amplify stress signals into physiological changes. A preponderance of preclinical data and clinical observations established p38αMAPK as a brain drug discovery target involved in neuroinflammatory responses and synaptic dysfunction in multiple degenerative and neuropsychiatric brain disorders. We summarize the discovery of highly selective, brain-penetrant, small molecule p38αMAPK inhibitors that are efficacious in diverse animal models of neurologic disorders. A crystallography and pharmacoinformatic approach to fragment expansion enabled the discovery of an efficacious hit. The addition of secondary pharmacology screens to refinement delivered lead compounds with improved selectivity, appropriate pharmacodynamics, and efficacy. Safety considerations and additional secondary pharmacology screens drove optimization that delivered the drug candidate MW01-18-150SRM (MW150), currently in early stage clinical trials. |
format | Online Article Text |
id | pubmed-6580366 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-65803662019-06-20 A Selective and Brain Penetrant p38αMAPK Inhibitor Candidate for Neurologic and Neuropsychiatric Disorders That Attenuates Neuroinflammation and Cognitive Dysfunction Roy, Saktimayee M. Minasov, George Arancio, Ottavio Chico, Laura W. Van Eldik, Linda J. Anderson, Wayne F. Pelletier, Jeffrey C. Watterson, D. Martin J Med Chem [Image: see text] The p38αMAPK is a serine/threonine protein kinase and a key node in the intracellular signaling networks that transduce and amplify stress signals into physiological changes. A preponderance of preclinical data and clinical observations established p38αMAPK as a brain drug discovery target involved in neuroinflammatory responses and synaptic dysfunction in multiple degenerative and neuropsychiatric brain disorders. We summarize the discovery of highly selective, brain-penetrant, small molecule p38αMAPK inhibitors that are efficacious in diverse animal models of neurologic disorders. A crystallography and pharmacoinformatic approach to fragment expansion enabled the discovery of an efficacious hit. The addition of secondary pharmacology screens to refinement delivered lead compounds with improved selectivity, appropriate pharmacodynamics, and efficacy. Safety considerations and additional secondary pharmacology screens drove optimization that delivered the drug candidate MW01-18-150SRM (MW150), currently in early stage clinical trials. American Chemical Society 2019-04-12 2019-06-13 /pmc/articles/PMC6580366/ /pubmed/30978288 http://dx.doi.org/10.1021/acs.jmedchem.9b00058 Text en Copyright © 2019 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
spellingShingle | Roy, Saktimayee M. Minasov, George Arancio, Ottavio Chico, Laura W. Van Eldik, Linda J. Anderson, Wayne F. Pelletier, Jeffrey C. Watterson, D. Martin A Selective and Brain Penetrant p38αMAPK Inhibitor Candidate for Neurologic and Neuropsychiatric Disorders That Attenuates Neuroinflammation and Cognitive Dysfunction |
title | A Selective and
Brain Penetrant p38αMAPK Inhibitor
Candidate for Neurologic and Neuropsychiatric Disorders That Attenuates
Neuroinflammation and Cognitive Dysfunction |
title_full | A Selective and
Brain Penetrant p38αMAPK Inhibitor
Candidate for Neurologic and Neuropsychiatric Disorders That Attenuates
Neuroinflammation and Cognitive Dysfunction |
title_fullStr | A Selective and
Brain Penetrant p38αMAPK Inhibitor
Candidate for Neurologic and Neuropsychiatric Disorders That Attenuates
Neuroinflammation and Cognitive Dysfunction |
title_full_unstemmed | A Selective and
Brain Penetrant p38αMAPK Inhibitor
Candidate for Neurologic and Neuropsychiatric Disorders That Attenuates
Neuroinflammation and Cognitive Dysfunction |
title_short | A Selective and
Brain Penetrant p38αMAPK Inhibitor
Candidate for Neurologic and Neuropsychiatric Disorders That Attenuates
Neuroinflammation and Cognitive Dysfunction |
title_sort | selective and
brain penetrant p38αmapk inhibitor
candidate for neurologic and neuropsychiatric disorders that attenuates
neuroinflammation and cognitive dysfunction |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580366/ https://www.ncbi.nlm.nih.gov/pubmed/30978288 http://dx.doi.org/10.1021/acs.jmedchem.9b00058 |
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