Potent Neuronal Nicotinamide Adenine Dinucleotide-Boosting Tetrahydroquinoxalines: Structure-Activity Relationships and Early Drug Metabolism and Pharmacokinetics Evaluation.

Overview

Authors: Petra Cuřínová¹, Melissa Jöe², Filip Cesar¹, Alan Nicol², Kristián Schwan¹, Michal Kohout¹, Carmine Varrichio³, Aljona Saleh⁴, Craig E Wheelock^5,6, Gauti Jóhannesson^2,7,8, Václav Eigner⁹, James R Tribble², Andrea Brancale¹, Pete A Williams^2,10

ORCID iDs: Petra Cuřínová, Alan Nicol, Michal Kohout, Craig E Wheelock, Andrea Brancale, Pete A Williams

Institutions: University of Chemistry and Technology, Prague (Czechia); Karolinska Institutet (Sweden); S:t Eriks Ögonsjukhus (Sweden); Cardiff University (United Kingdom); Science for Life Laboratory (Sweden); Karolinska University Hospital (Sweden); University of Iceland (Iceland); Umeå University (Sweden); The Royal Victorian Eye & Ear Hospital (Australia); Centre for Eye Research Australia (Australia)

Journal: ACS medicinal chemistry letters, volume 17, issue 4, pages 916-924

Dates: received 30 January 2026; accepted 26 February 2026; published online 4 March 2026

Type: Research article · Language: English

License: CC BY

Identifiers: DOI 10.1021/acsmedchemlett.6c00058 · PMID 41982735 · PMCID PMC13071616 · OpenAlex W7133537791

Open access: hybrid, a free copy (OpenAlex)

Status: data only

Keywords: Neurodegeneration, NAD metabolism, NMNAT2, tetrahydroquinoxaline derivatives

Topic: Chemical Reactions and Isotopes (Pharmaceutical Science, Pharmacology, Toxicology and Pharmaceutics), according to OpenAlex

Funding: Glaucoma Foundation; BrightFocus Foundation; Petrus och Augusta Hedlunds Stiftelse; Karolinska Institutet (2022-00799); Novo Nordisk; Vetenskapsrådet (2022-00799); Novo Nordisk Fonden; S:t Eriks Ögonforskningsstiftelse

Citations: not cited yet (Europe PMC); 21 references in the paper

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

zenodo:18863613, at Zenodo; found in DataCite
zenodo:18863614, at Zenodo; found in DataCite

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 14 authors, 4 keywords, 8 funders, 18 references.

Cite

This paper

Cuřínová, P., Jöe, M., Cesar, F., Nicol, A., Schwan, K., Kohout, M., Varrichio, C., Saleh, A., Wheelock, C. E., Jóhannesson, G., Eigner, V., Tribble, J. R., Brancale, A., & Williams, P. A. (2026). Potent Neuronal Nicotinamide Adenine Dinucleotide-Boosting Tetrahydroquinoxalines: Structure-Activity Relationships and Early Drug Metabolism and Pharmacokinetics Evaluation. ACS medicinal chemistry letters, 17(4), 916-924. https://doi.org/10.1021/acsmedchemlett.6c00058

BibTeX

@article{curinova2026potent, author = {Cuřínová, Petra and Jöe, Melissa and Cesar, Filip and Nicol, Alan and Schwan, Kristián and Kohout, Michal and Varrichio, Carmine and Saleh, Aljona and Wheelock, Craig E and Jóhannesson, Gauti and Eigner, Václav and Tribble, James R and Brancale, Andrea and Williams, Pete A}, title = {{Potent Neuronal Nicotinamide Adenine Dinucleotide-Boosting Tetrahydroquinoxalines: Structure-Activity Relationships and Early Drug Metabolism and Pharmacokinetics Evaluation}}, journal = {ACS medicinal chemistry letters}, year = {2026}, month = mar, volume = {17}, number = {4}, pages = {916--924}, publisher = {American Chemical Society}, issn = {1948-5875}, doi = {10.1021/acsmedchemlett.6c00058}, url = {https://doi.org/10.1021/acsmedchemlett.6c00058}, pmid = {41982735}, pmcid = {PMC13071616} }

RIS

TY - JOUR AU - Cuřínová, Petra AU - Jöe, Melissa AU - Cesar, Filip AU - Nicol, Alan AU - Schwan, Kristián AU - Kohout, Michal AU - Varrichio, Carmine AU - Saleh, Aljona AU - Wheelock, Craig E AU - Jóhannesson, Gauti AU - Eigner, Václav AU - Tribble, James R AU - Brancale, Andrea AU - Williams, Pete A TI - Potent Neuronal Nicotinamide Adenine Dinucleotide-Boosting Tetrahydroquinoxalines: Structure-Activity Relationships and Early Drug Metabolism and Pharmacokinetics Evaluation T2 - ACS medicinal chemistry letters J2 - ACS Med Chem Lett PY - 2026 DA - 2026/03/04 VL - 17 IS - 4 SP - 916 EP - 924 SN - 1948-5875 PB - American Chemical Society DO - 10.1021/acsmedchemlett.6c00058 UR - https://doi.org/10.1021/acsmedchemlett.6c00058 LA - en ER -

CSL-JSON

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