Potent neuronal nicotinamide adenine dinucleotide-boosting tetrahydroquinoxalines: Structure–activity relationships and early drug metabolism and pharmacokinetics evaluation

Cuřínová, Petra, Jöe, Melissa, Cesar, Filip, Nicol, Alan, Schwan, Kristián, Kohout, Michal, Varricchio, Carmine ORCID: https://orcid.org/0000-0002-1673-4768, Saleh, Aljona, Wheelock, Craig E., Jóhannesson, Gauti, Eigner, Václav, Tribble, James R., Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419 and Williams, Pete A. 2026. Potent neuronal nicotinamide adenine dinucleotide-boosting tetrahydroquinoxalines: Structure–activity relationships and early drug metabolism and pharmacokinetics evaluation. ACS Medicinal Chemistry Letters 10.1021/acsmedchemlett.6c00058

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Abstract

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.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Pharmacy
Publisher:	American Chemical Society
ISSN:	1948-5875
Date of First Compliant Deposit:	24 March 2026
Date of Acceptance:	26 February 2026
Last Modified:	24 Mar 2026 10:30
URI:	https://orca.cardiff.ac.uk/id/eprint/185979

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