HDAC6-IN-69 is a highly selective HDAC6 inhibitor capable of crossing the blood-brain barrier, with an IC50 of 4.0 nM and more than 176-fold selectivity over other HDAC isoforms. It upregulates acetylated α-tubulin levels in neuronal cells in a dose-dependent manner, providing neuroprotective effects and is applicable for ischemic stroke research.

HDAC1:1135 nM

HDAC6-IN-69 (compound 8k) demonstrates favorable pharmacokinetic properties, exhibiting moderate clearance and metabolic stability in both human and rat liver microsomes (human liver microsome half-life T 1/2 = 154.00 min, rat liver microsome half-life T 1/2 = 29.49 min), and poses a low risk of cardiac toxicity. At concentrations of 1.0-10 μM over 24 hours, HDAC6-IN-69 selectively inhibits HDAC6 over HDAC1 in human neuroblastoma cells (SH-SY5Y cells). Furthermore, when pre-treated at 0.1-10 μM for 0.5 hours, it shows potential neuroprotective activity in a L-glutamate-induced SH-SY5Y cell injury model.

HDAC6-IN-69 (compound 8k) (administered intravenously at doses of 6 or 12.5 mg/kg, single dose) demonstrates significant potential in reducing cerebral infarction caused by stroke in a rat model of middle cerebral artery occlusion.