Pharmacological Characterization and Preclinical Evaluation of 11h: A Novel, Brain-Penetrant PDE4 Inhibitor for Neurological Disorders

Jacob Lackovic^1*Sougata Dey¹Sara Jane Ward²Nigel H Greig³David Tweedie³Nassim Beiranvand⁴Uksha Saini¹Dev Chatterjee^1*Atul Varadhachary^1*

• ¹Fannin Partners LLC, Houston, United States
• ²Temple University, Philadelphia, United States
• ³National Institute on Aging Intramural Research Program, Baltimore, United States
• ⁴Texas Medical Center, Houston, United States

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 11h, a novel, orally available, brain-penetrant PDE4 inhibitor designed to address these limitations. 11h demonstrated potent, broad-spectrum inhibition across all four PDE4 isoforms, including key PDE4D splice variants (PDE4D2, PDE4D3), with low nanomolar IC₅₀ values. In vitro, 11h significantly reduced the release of tumor necrosis factor alpha (TNFα), interleukin 6 (IL-6), and nitrites in lipopolysaccharide (LPS)-stimulated macrophages, microglia-like cells, and human peripheral blood mononuclear cells without affecting cell viability. In vivo, 11h attenuated neuroinflammation in LPS-treated mice by decreasing M1 macrophages and CD4⁺ T cells, increasing M2 macrophages, and downregulating pro-inflammatory cytokines and MyD88 pathway genes. Pharmacokinetic analysis in rats confirmed strong oral bioavailability, dose-proportional systemic exposure, and sustained brain concentrations exceeding plasma levels for up to 48 hours post-dose. Importantly, 11h did not induce vomiting in the ferret emesis model even at doses exceeding 50-fold the efficacious levels in rodent disease models, and was well tolerated in behavioral assays, where it produced anxiolytic-and antidepressant-like effects. Safety profiling revealed no cytotoxicity, genotoxicity, or significant inhibition of cardiac ion channels or cytochrome P450 enzymes. Consistent with this experimental profile, molecular docking suggested that 11h preferentially engages a pocket within the PDE4 catalytic domain, with high predicted binding affinity and ligand efficiency driven by hydrophobic and electrostatic interactions.These findings, which suggest that 11h offers broad PDE4 inhibition with improved tolerability and pharmacokinetic properties relative to approved PDE4 inhibitors, support advancing 11h as a promising therapeutic candidate for CNS disorders characterized by neuroinflammation.