ArticleFrontiers in pharmacology2025
Pharmacological characterization and preclinical evaluation of 11h: a novel, brain-penetrant PDE4 inhibitor for neurological disorders.
Article in Frontiers in pharmacology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- The lung-brain axis in neurodegeneration: inflammatory, immune, and vascular mechanisms with therapeutic implications.Inflammopharmacology · 2026Review
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9 authors.
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Abstract
Background: Phosphodiesterase 4 (PDE4) inhibitors hold promise for treating neuroinflammatory and neurodegenerative disorders, but their clinical application in central nervous system (CNS) diseases has been limited by insufficient brain penetration and adverse effects, especially nausea and vomiting. In this study, we characterize compound 11h, a novel, orally available, brain-penetrant PDE4 inhibitor designed to address these limitations. Methods: 11h was evaluated using integrated computational, in vitro, and in vivo approaches, including Schrödinger-based molecular docking against human PDE4A10, luminescence-based cAMP assays for PDE4 isoform inhibition, and inflammatory assays in murine macrophages, microglia-like cells, and human PBMCs. In vivo efficacy, pharmacokinetics, brain and tissue distribution, tolerability, emesis liability, and behavioral effects were assessed across mouse, rat, and ferret models, alongside comprehensive safety pharmacology encompassing CYP450 inhibition, cardiac ion channel profiling, mutagenicity, and off-target screening. Results: 11h demonstrated potent, broad-spectrum inhibition across all four PDE4 isoforms, including key PDE4D splice variants (PDE4D2, PDE4D3), with low nanomolar IC50 values. Conclusion: These findings suggest that 11h provides broad PDE4 inhibition with a favorable tolerability and pharmacokinetic profile relative to approved PDE4 inhibitors, supporting its further development as a therapeutic candidate for CNS disorders characterized by neuroinflammation.
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