Targeting Dysregulated Neuroinflammation in CNS Disorders

Abstract

A critical mechanism driving neurodegenerative disease progression is dysregulated brain inflammation. Neuroinflammatory repair processes are fundamental to CNS homeostasis, but inflammation that is inefficient, excessive, or prolonged can contribute to neurodegeneration. A specific aspect of neuroinflammation, stressor-induced proinflammatory cytokine overproduction from abnormally activated glia, has been linked to subsequent neurological damage and cognitive deficits in both acute and chronic CNS disorders. This cytokine/synaptic dysfunction axis (Fig. 1) has emerged as an attractive druggable target for neurodegenerative diseases. However, despite advances in our understanding of these molecular neuroinflammatory mechanisms, approved therapeutics that target this pathological process are lacking. To address this need, we used an integrated, recursive drug discovery platform (Fig. 2) to develop brain-penetrant, small molecule drug candidates that normalize cytokine levels and exhibit efficacy at low doses in multiple animal models of CNS disorders. The molecule design stage began with a pyridazine chemotype that was diversified using established chemistries to create a library of compounds. Compounds were screened for concentration dependence and selectivity using either a single molecular target approach or the historically successful functional/pathway-based approach. A pharmacology assessment stage was incorporated to assess compounds for drug-like properties, such as chemical and metabolic stability, CNS penetrance, and potential for safety. Prioritized compounds were then tested in relevant animal models, and the most promising drug candidates taken into formal IND-enabling preclinical testing. The platform yielded three clinical drug candidates, MW150, MW151, and MW189, that are all in human phase 1b/2a clinical trials.