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[P3–056]: SELECTIVE PKR INHIBITION RESCUES MEMORY DEFICITS AND NEURODEGENERATION IN MOUSE MODELS WITH PATHOLOGICAL FEATURES OF ALZHEIMER's DISEASE
Author(s) -
Ibghi Delphine,
LopezGrancha Mati,
Bernardelli Patrick,
Moindrot Nicolas,
Goniot Philippe,
Genet Elisabeth,
Roudieres Valérie,
Vincent Carine,
Taupin Veronique
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.06.1266
Subject(s) - morris water navigation task , protein kinase r , neurodegeneration , neuroinflammation , endocrinology , medicine , protein kinase a , kinase , neuroscience , chemistry , biology , microbiology and biotechnology , disease , hippocampus , mitogen activated protein kinase kinase
focused on synaptic dysfunction and innate immunity as a common pathophysiology progression theme, we developed a platform that delivers new in vivo molecular probes of different potential therapeutic intervention mechanisms. Methods: The platform is based on highly focused organic syntheses of new chemical entities designed by risk reduction using pharmacoinformatics combined with project-specific considerations. Key among pharmacoinformatic restrictions were multi-property profiles based on curated databases of in vivo CNS drugs and drug candidates. Initial sets of synthesized compounds were taken through non-GLP ADMETbased pharmacological screens as a Go or NoGo decision point. Compounds passing Go were taken through hierarchical screens of activity related to pharmacological mechanism and in vivo efficacy. A prototype single molecular target approach for CNS protein kinases was brain p38aMAPK, an established target whose activity is up-regulated in glia and neurons in stress responses. The phenotypic approach focused on early stage overproduction of proinflammatory cytokines causally linked to synaptic dysfunction. Results: The case study presentations are those based on an aminoarylpyridazine molecular fragment and its chemical diversification. Novel small molecule deliverables for each pharmacological intervention approach show efficacy in AD-relevant mouse models. Conclusions:Our validated discovery platform has generated efficacious, CNS-active, in vivo molecular probes. ADMET-optimized versions of these probes are in late stage, investigational new drug (IND) development or early stage first-in-human clinical trials.