Potent Neuronal Nicotinamide Adenine Dinucleotide-Boosting Tetrahydroquinoxalines: Structure-Activity Relationships and Early Drug Metabolism and Pharmacokinetics Evaluation.
JSON
Cuřínová P, Jöe M, Cesar F, Nicol A, Schwan K, Kohout M, Varrichio C, Saleh A, Wheelock CE, Jóhannesson G, Eigner V, Tribble JR, Brancale A, Williams PA
ACS Med Chem Lett 17 (4) 916-924 [2026-04-09; online 2026-03-04]
We designed and synthesized a series of novel 1,2,3,4-tetrahydroquinoxaline derivatives and evaluated their ability to increase nicotinamide adenine dinucleotide (NAD) levels in primary cortical neurons. Several compounds demonstrated nanomolar potency and enabled the establishment of clear structure-activity relationships (SAR), highlighting key substituents required for activity. Qualitative 3DSAR analysis further identified favorable steric, electrostatic, and hydrophobic features associated with NAD enhancement. Selected lead compounds were assessed for in vitro drug metabolism and pharmacokinetics (DMPK) properties, showing good cell permeability and species-dependent metabolic stability in liver microsomes, with improved stability in human systems compared with rodent systems. These findings identify tetrahydroquinoxalines as a promising class of neuronal NAD-boosting agents and provide a strong foundation for further optimization toward neuroprotective drug candidates.
Drug Discovery and Development [Service]
PubMed 41982735
DOI 10.1021/acsmedchemlett.6c00058
Crossref 10.1021/acsmedchemlett.6c00058