The futility of the familiar: rethinking strategies for the development of small molecules for neurodegenerative disorders.

Abstract

INTRODUCTION: As life expectancy increases globally, the prevalence of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases continues to rise. Despite decades of intensive research and substantial investment, effective preventive or curative treatments remain unavailable. Much of the drug discovery efforts has focused on small-molecule therapeutics. However, these approaches have yielded limited clinical success. This lack of progress underscores the inherent complexity of neurodegenerative diseases and suggests that conventional drug discovery paradigms may be overly simplistic or fundamentally flawed. AREAS COVERED: In this article, the authors explore the key challenges underlying the failure of small-molecule strategies in neurodegenerative research and discuss emerging avenues that may offer more promising therapeutic outcomes for brain disorders. EXPERT OPINION: Conventional approaches in CNS drug discovery and development have not yielded disease-modifying CNS drugs. To be successful, it is important to rethink strategies, assays, animal models from scratch and redesign how R&D in CNS diseases should be carried out.