Indolizine cap group delivers a selective HDAC6 inhibitor that calms neuronal inflammation
- The authors used an indolizine as a new cap group within the standard HDAC pharmacophore and made a 13-member series.
- SAR showed that decorating the cap group is key to balancing potency and isoform selectivity; indostat (5g) emerged as the best compound, with balanced solubility, stability and lipophilicity.
- In hippocampal neurons stimulated with poly(I:C), indostat lowered IL-6 secretion and normalized the rise in HDAC6 activity.
- Anti-inflammatory effect matched pan-HDAC inhibitor SAHA, with better cellular tolerability.
💡 Points Based on the abstract
Matching SAHA on IL-6 is a low bar for a selective HDAC6 compound; I'd add a tubastatin-type benchmark and HDAC6 knockdown to show the effect is on-target. Indolizine is an easy cap to decorate, but electron-rich ring systems can be oxidation-prone, so I'd check oxidative and photostability early.
📄 Paper · European Journal of Medicinal Chemistry ↗ Identification of Indostat as a selective HDAC6 inhibitor for reducing inflammatory stimuli triggered by a synthetic analogue of viral double-stranded RNA in hippocampal neurons