New Oral CD38 Inhibitors Boost NAD+ with Brain-Penetrating Power
Scientists developed potent, orally bioavailable CD38 inhibitors that engage targets across skin, lung, liver, and brain — opening new NAD+ longevity research avenues.
Summary
Researchers at AbbVie and Sygnature Discovery discovered a new class of small molecule inhibitors targeting CD38, an enzyme that degrades NAD+ — a molecule central to cellular energy and aging. Starting from a virtual ligand screen, they optimized an initial hit into two key compounds: A-8531, a potent peripheral tool compound, and A-3190, a brain-penetrating variant. Both showed strong pharmacokinetics in rodents and demonstrated measurable target engagement in multiple tissues including the brain. CD38 activity rises with age and is a major driver of NAD+ decline, so these inhibitors represent important research tools and potential therapeutic leads for age-related diseases affecting the brain and body.
Detailed Summary
NAD+ is a critical coenzyme involved in energy metabolism, DNA repair, and cellular signaling, and its levels decline markedly with age. CD38, a cell-surface enzyme that consumes NAD+, is one of the primary culprits behind this age-related decline. Inhibiting CD38 has therefore emerged as a promising strategy to restore NAD+ levels and potentially slow aspects of biological aging.
In this study, researchers from AbbVie and Sygnature Discovery used virtual ligand screening to identify an imidazopyridazine scaffold as a starting point for CD38 inhibition. Through iterative structure- and property-based optimization, they developed compound A-8531 (compound 25), a potent CD38 inhibitor with excellent oral pharmacokinetics suited for peripheral tissue studies.
Crystal structure analysis and biochemical characterization revealed that A-8531 acts through uncompetitive inhibition, forming a covalent adduct with CD38. This mechanistic insight guided further optimization toward A-3190 (compound 39), a sulfuryl pyrazole thienopyrimidine analog with significantly improved CNS penetration properties.
In rodent models, A-3190 demonstrated robust pharmacokinetics and confirmed target engagement across skin, lung, liver, and brain — making it particularly valuable for studying CD38's role in neurological and systemic age-related conditions. These brain-penetrant properties are a notable advance, as most prior CD38 inhibitor research has focused on peripheral tissues.
While these compounds are currently research tools rather than clinical candidates, their discovery marks meaningful progress toward drugging the CD38-NAD+ axis for aging and neurodegeneration. Key caveats include the early-stage, preclinical nature of the findings and limited data on long-term safety or efficacy in disease models.
Key Findings
- Virtual ligand screening identified an imidazopyridazine scaffold optimized into potent CD38 inhibitor A-8531 with strong oral bioavailability.
- A-8531 acts via uncompetitive, covalent inhibition of CD38, confirmed by co-crystal structure analysis.
- A-3190 achieved brain penetration with robust rodent pharmacokinetics and target engagement in skin, lung, liver, and brain.
- Both compounds serve as valuable preclinical tools for studying CD38's role in NAD+ decline and aging.
- Brain-penetrant CD38 inhibition opens research avenues for neurodegenerative and CNS-related age-related diseases.
Methodology
The study used virtual ligand screening to identify hit compounds, followed by iterative medicinal chemistry optimization guided by co-crystal structures, biophysical assays, and biochemical characterization. Rodent pharmacokinetic studies and in vivo target engagement assays across multiple tissues were used to evaluate lead compounds.
Study Limitations
These are preclinical tool compounds and have not been evaluated in human clinical trials or chronic disease models. The covalent mechanism of inhibition may raise selectivity and safety concerns requiring further investigation. Efficacy in actual age-related disease endpoints has not yet been demonstrated.
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