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.
Successful completion of the proposed investigations will provide novel, efficacious compounds required for clinical development of new therapies for neurological disorders.
|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 p38? 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|
|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|
|Bachstetter, Adam D; Xing, Bin; de Almeida, Lucia et al. (2011) Microglial p38ýý MAPK is a key regulator of proinflammatory cytokine up-regulation induced by toll-like receptor (TLR) ligands or beta-amyloid (Aýý). J Neuroinflammation 8:79|
|Chen, Tian; Benmohamed, Radhia; Arvanites, Anthony C et al. (2011) Arylsulfanyl pyrazolones block mutant SOD1-G93A aggregation. Potential application for the treatment of amyotrophic lateral sclerosis. Bioorg Med Chem 19:613-22|
|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|
|Chico, Laura K; Van Eldik, Linda J; Watterson, D Martin (2009) Targeting protein kinases in central nervous system disorders. Nat Rev Drug Discov 8:892-909|
|Chico, Laura K; Behanna, Heather A; Hu, Wenhui et al. (2009) Molecular properties and CYP2D6 substrates: central nervous system therapeutics case study and pattern analysis of a substrate database. Drug Metab Dispos 37:2204-11|