A Selective and Brain Penetrant p38αMAPK Inhibitor Candidate for Neurologic and Neuropsychiatric Disorders That Attenuates Neuroinflammation and Cognitive Dysfunction

Saktimayee M. Roy, George Minasov, Ottavio Arancio, Laura W. Chico, Linda J. Van Eldik, Wayne F. Anderson, Jeffrey C. Pelletier, D. Martin Watterson

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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 languageEnglish
Pages (from-to)5298-5311
Number of pages14
JournalJournal of Medicinal Chemistry
Volume62
Issue number11
DOIs
StatePublished - Jun 13 2019

Bibliographical note

Funding Information:
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.

Publisher Copyright:
© 2019 American Chemical Society.

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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