Central nervous system (CNS) drugs comprise 20-25% of all prescriptions dispensed annually in the United States. An estimated 100 million Americans suffer from devastating brain disorders such as stroke, epilepsy, depression, migraine, Alzheimer’s disease, and other dementias at some point in their lives. The prevalence of CNS disorders is ever increasing with the aging population, causing a heavy burden on our healthcare systems. In 2020, Alzheimer’s and other dementias cost the nation $305 billion, and by 2050, these costs could rise to as high as $1.1 trillion. Despite the enormous need for effective therapies, the successful development and approval of novel CNS drugs remain exceedingly slow. One of the fundamental challenges unique to CNS drug development is achieving adequate drug concentrations at the target delivery site. The systemic delivery of drugs into the brain is regulated by the blood-brain barrier (BBB). While the BBB is critical for maintaining the brain’s homeostasis by protecting against toxic agents, it represents a significant obstacle for the systemic delivery of drugs to the CNS. Over the years, tremendous research efforts have provided useful insights into the physicochemical and structural preferences of drugs with adequate BBB permeability. This critical knowledge is also valuable for developing non-CNS drugs to avoid undesirable distribution to the brain. In 2011, Ghosh et al. published property-based guidelines for distinguishing CNS and non-CNS drugs using 317 CNS and 626 non-CNS drugs approved prior to 2010. In this retrospective study, we have analyzed 192 CNS and non-CNS drugs newly approved by the FDA from 2010 to 2020, using cheminformatic approaches. The results, providing updated guidelines based on physicochemical and structural properties for optimal BBB permeability, will be presented. These revised guidelines will be useful for lead selection and optimization in the early-stage discovery of potential CNS and non-CNS drugs.

Knowledge-based prediction of CNS permeability of drugs

ACS Spring Meeting 2021

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