The long-term goal of this research program is the discovery of potentially disease-modifying therapies for neurodegenerative disorders. This proposal tests the hypothesis that novel p38 MAPK inhibitors that are orally bioavailable, have good brain uptake, and are non-toxic can be developed into a new class of therapeutics for CNS disorders. The proposed research seeks to develop p38 MAPK inhibitors that can restore pathology associated increased proinflammatory cytokine production toward basal levels with positive neurologic outcomes in animal models. The linkage to the long term goals is that the deliverables emerging from successful completion of the proposed studies will form the foundation of follow-on drug development campaigns for neurodegenerative disorders. Clinical studies have provided a linkage among neurodegenerative disorders, glia activation and increased levels of proinflammatory cytokines, with feasibility studies using macromolecular therapeutics suggestive of a positive clinical effect of proinflammatory cytokine attenuation in Alzheimer's disease. Prior art in animal models has demonstrated a pathophysiology progression role and enhanced sensitivity to synaptic dysfunction and neurologic deficits in animal models where brain proinflammatory cytokine levels are increased. Attenuation of neurologic deficits can be restored by inhibiting the increase in proinflammatory cytokine production. Therefore, an accumulating body of evidence indicates the potential of targeting proinflammatory cytokine up-regulation for attenuation of CNS dysfunction. However, there is an unmet need for bioavailable, CNS-penetrant small molecules amenable to clinical development. We propose to use our integrative drug discovery platform that combines """"""""smart"""""""" chemistry with """"""""smart"""""""" biology to discover novel lead compounds with attractive physical properties and high potential for CNS penetrance, safety and efficacy, followed by medicinal chemistry refinement into candidates for future clinical development. The molecular target is the serine/threonine protein kinase p381MAPK, a key regulator of proinflammatory cytokine production and an established therapeutic target for peripheral tissue diseases where increased proinflammatory cytokine levels are part of the disease progression mechanism. Specifically, we propose to: design, synthesize, and refine novel p381MAPK inhibitors with potential for oral bioavailability and CNS penetrance;screen compounds to identify orally bioavailable, CNS-penetrant, non-toxic, stable lead compounds that are selective suppressors of increased cytokine production in the brain;and test selected lead compounds for efficacy in Alzheimer's disease-relevant animal models. Successful completion of the proposed investigations will provide a knowledgebase and novel lead compounds for future IND-enabling preclinical toxicology and pharmacokinetics required for initiation of later clinical investigations.

Public Health Relevance

Successful completion of the proposed investigations will provide novel, efficacious compounds required for clinical development of new therapies for neurological disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG031311-05
Application #
8286256
Study Section
Special Emphasis Panel (ZRG1-MDCN-N (02))
Program Officer
Refolo, Lorenzo
Project Start
2008-08-01
Project End
2013-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$293,487
Indirect Cost
$99,125
Name
Northwestern University at Chicago
Department
Type
Organized Research Units
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Roy, Saktimayee M; Grum-Tokars, Valerie L; Schavocky, James P et al. (2015) Targeting human central nervous system protein kinases: An isoform selective p38αMAPK inhibitor that attenuates disease progression in Alzheimer's disease mouse models. ACS Chem Neurosci 6:666-80
Bachstetter, Adam D; Watterson, D Martin; Van Eldik, Linda J (2014) Target engagement analysis and link to pharmacodynamic endpoint for a novel class of CNS-penetrant and efficacious p38α MAPK inhibitors. J Neuroimmune Pharmacol 9:454-60
Morfini, Gerardo A; Bosco, Daryl A; Brown, Hannah et al. (2013) Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase. PLoS One 8:e65235
Watterson, D Martin; Grum-Tokars, Valerie L; Roy, Saktimayee M et al. (2013) Development of Novel In Vivo Chemical Probes to Address CNS Protein Kinase Involvement in Synaptic Dysfunction. PLoS One 8:e66226
Chico, Laura K; Watterson, Daniel Martin (2012) The 6th drug discovery for neurodegeneration conference: an intensive course on translating research into drugs. Expert Opin Drug Discov 7:1225-8
Bachstetter, Adam D; Norris, Christopher M; Sompol, Pradoldej et al. (2012) Early stage drug treatment that normalizes proinflammatory cytokine production attenuates synaptic dysfunction in a mouse model that exhibits age-dependent progression of Alzheimer's disease-related pathology. J Neurosci 32:10201-10
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Ross, Brian; Tran, Thao; Bhattacharya, Pratip et al. (2011) Application of NMR spectroscopy in medicinal chemistry and drug discovery. Curr Top Med Chem 11:93-114
McNamara, Laurie K; Brunzelle, Joseph S; Schavocky, James P et al. (2011) Site-directed mutagenesis of the glycine-rich loop of death associated protein kinase (DAPK) identifies it as a key structure for catalytic activity. Biochim Biophys Acta 1813:1068-73
Mirzapoiazova, Tamara; Moitra, Jaideep; Moreno-Vinasco, Liliana et al. (2011) Non-muscle myosin light chain kinase isoform is a viable molecular target in acute inflammatory lung injury. Am J Respir Cell Mol Biol 44:40-52

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