First-in-Class Hydrazide-Based HDAC6 Selective Inhibitor with Potent Oral Anti-Inflammatory Activity by Attenuating NLRP3 Inflammasome Activation

In
this study, we report the first highly selective HDAC6 inhibitor
with hydrazide as the zinc-binding group (ZBG), which displays superior
pharmacokinetic properties to the current hydroxamic acid inhibitors.
Structure–activity relationship study reveals that ethyl group
substituent hydrazide-based ZBG and cap group with more substantial
rigidity and larger volume increase the HDAC6 selectivity of designed
compounds. Representative inhibitor 35m exhibits potent
HDAC6 inhibitory activity with an IC50 value of 0.019 μM.
To our surprise, 35m establishes significant improvement
in the pharmacokinetic property with much higher AUC0‑inf (10292 ng·h/mL) and oral bioavailability (93.4%) than hydroximic
acid-based HDAC6 inhibitors Tubastatin A and ACY-1215. Low-dose 35m remarkably decreases LPS-induced IL-1β release both in vitro and in vivo by blocking the activation
of NLRP3, indicating that 35m can be a potential orally
active therapeutic agent for the treatment of NLRP3-related diseases.