AEX-41

AEX-41 is a first-in-class, highly selective dual orexin receptor agonist (DOXA) that targets both orexin-1 (OX1R) and orexin-2 (OX2R) receptors. It is a non-sulfonamide small molecule designed to promote wakefulness and improve sleep architecture by mimicking the action of endogenous orexins. In addition to its primary activity as an OX1R and OX2R agonist, AEX-41 also inhibits cathepsin H (CTSH), an enzyme implicated in neurodegenerative processes and neuroinflammation. Preclinical studies have demonstrated that oral administration of AEX-41 increases wakefulness and reduces REM sleep duration in orexin knockout mouse models of narcolepsy, with efficacy comparable to existing selective OX2R agonists. The drug also shows potential for broader application in neurological disorders due to additional engagement with the Sigma-1 receptor and mitochondrial regulation pathways. Developed by NLS Pharmaceutics, research on AEX-41 is currently at the preclinical stage with plans for IND-enabling studies targeting CNS disorders such as narcolepsy, idiopathic hypersomnia, neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), and diabetes-associated neurological dysfunction[3][4][5][7][10].