Abstract
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.
Original language | English (US) |
---|---|
Pages (from-to) | 5298-5311 |
Number of pages | 14 |
Journal | Journal of Medicinal Chemistry |
Volume | 62 |
Issue number | 11 |
DOIs | |
State | Published - Jun 13 2019 |
Funding
This research was supported in part by NIH Awards U01AG043415, R01NS056051, R01AG031311, and R01NS093920 as well as ADDF Award 261108. We thank Dr. Christos D. Malliakas for his assistance with crystallographic structure and physical property studies of compound 11 and James Schavocky for his assistance and help with manuscript preparation.
ASJC Scopus subject areas
- Drug Discovery
- Molecular Medicine
Fingerprint
Dive into the research topics of 'A Selective and Brain Penetrant p38αMAPK Inhibitor Candidate for Neurologic and Neuropsychiatric Disorders That Attenuates Neuroinflammation and Cognitive Dysfunction'. Together they form a unique fingerprint.Datasets
-
Structure of human p38aMAPK-arylpyridazinylpyridine fragment complex used in inhibitor discovery
Roy, S. M. (Contributor), Minasov, G. (Contributor), Arancio, O. (Contributor), Chico, L. W. (Contributor), Van Eldik, L. J. (Contributor), Anderson, W. F. (Contributor), Pelletier, J. C. (Contributor) & Watterson, D. M. (Contributor), Protein Data Bank (PDB), Jun 22 2016
DOI: 10.2210/pdb4ZTH/pdb, https://www.wwpdb.org/pdb?id=pdb_00004zth
Dataset
-
Human p38 alpha MAPK in complex with a pyridazine based inhibitor
Munoz, L. (Contributor), Ranaivo, H. (Contributor), Roy, S. M. (Contributor), Hu, W. (Contributor), Craft, J. M. (Contributor), McNamara, L. K. (Contributor), Chico, L. W. (Contributor), Van Eldik, L. J. (Contributor), Watterson, D. M. (Contributor), Minasov, G. (Contributor), Arancio, O. (Contributor), Anderson, W. F. (Contributor) & Pelletier, J. C. (Contributor), Protein Data Bank (PDB), Jun 27 2012
DOI: 10.2210/pdb4EWQ/pdb, https://www.wwpdb.org/pdb?id=pdb_00004ewq
Dataset
-
CCDC 1851509: Experimental Crystal Structure Determination
Roy, S. M. (Contributor), Watterson, D. M. (Contributor) & Malliakas, C. (Contributor), Cambridge Crystallographic Data Centre, 2018
DOI: 10.5517/ccdc.csd.cc204n3y, http://www.ccdc.cam.ac.uk/services/structure_request?id=doi:10.5517/ccdc.csd.cc204n3y&sid=DataCite
Dataset