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P1‐304: An optimized and isoform‐selective p38aMAPK inhibitor that attenuates disease progression in Alzheimer's disease mouse models
Author(s) -
Eldik Linda J.,
Roy Saktimayee M.,
Watterson D. Martin,
Arancio Ottavio
Publication year - 2015
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.2015.06.519
Subject(s) - neuroscience , drug discovery , kinome , mapk/erk pathway , drug repositioning , disease , p38 mitogen activated protein kinases , hippocampal formation , drug development , neuropharmacology , pharmacology , medicine , kinase , computational biology , bioinformatics , biology , drug , microbiology and biotechnology
Background: Stress-induced activation of p38aMAPK in both neurons and glia raises a novel therapeutic hypothesis whereby enhanced efficacy might be generated via targeting a common target in two distinct cell types involved in a pathophysiological axis. However, pursuit of this neurotherapeutic hypothesis requires kinase isofor-selective inhibitors with appropriate neuropharmacology features. Methods: A scaffold repurposing approach employed high-resolution crystallography of complexes containing human p38aMAPK, driven by pharmacoinformatics-based design. Novel inhibitors were synthesized and filtered based on activity, pharmacological screening, and efficacy in Alzheimer’s disease (AD)-relevant mouse models in order to select best-in-class candidates. Results: We report an optimized, isoform-selective p38aMAPK inhibitor, MW01-18-150SRM (1⁄4 MW150) that has attractive pharmacological and functional features that render it a promising candidate for preclinical drug development. Highresolution crystallography documents MW150 active site binding and suggests a structural explanation for MW150’s exquisite kinome selectivity. Screens for target engagement, selectivity and property compliance with ICH guidelines indicate the high development potential of MW150. MW150 is efficacious in suppression of hippocampal-dependent associative and spatial memory deficits in two independent AD synaptic dysfunction mouse models when administered either before full-fledged pathology is evident or after pathology is present. Conclusions: MW150 is a highly selective p38aMAPK inhibitor that attenuates synaptic and cognitive dysfunction in AD-relevant mouse models, and shows potential for use in either a prevention mode or disease treatment mode. The successful medicinal chemistry optimization campaign and pharmacological de-risking of MW150 render it appropriate for investigational new drug (IND) enabling development.