ACY-775

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

ACY-775 (ACY775) 是一种有效且特异性的 HDAC6 抑制剂 (IC50=7.5 nM)，具有改善的大脑生物利用度。

ACY-775 (ACY775) is a potent and specific HDAC6 inhibitor (IC50=7.5 nM) with improved brain bioavailability; 60-1500 fold selectivity over class I HDACs; no activity against all other class II HDAC isoforms (IC50>1?uM); induce dramatic increases in α-tubulin acetylation in brain and stimulate mouse exploratory behaviors; increases the innervation of the neuromuscular junctions in the gastrocnemius muscle and improves the motor and sensory nerve conduction in the mutant HSPB1-induced CMT2 mouse model.

In vehicle-treated cells, α-tubulin is mainly presented in the deacetylated form, while histone 3 is clearly acetylated. Upon treatment with ACY-775, a clear enhancement of the acetylation of α-tubulin is visible, while histone acetylation remains unaltered. Acetylation of α-tubulin is visualized by immunofluorescence and the intensity in the neurites of the neurons is quantified and normalized to the length of the fluorescent signal. In vehicle-treated DRG neurons, acetylated α-tubulin is already present. Upon treatment with ACY-775 the signal intensity of acetylated α-tubulin increases significantly. Significant increase in motility of mitochondria and also the total number of mitochondria within the neurites are observed compare with vehicle-treated DRG neurons. A significantly higher number of retrogradely transport mitochondria is observed in DRG neurons treated with ACY-775 compare with vehicle-treated cells.

Biodistribution profiles of ACY-738, ACY-775, and tubastatin A are examined after acute dosing at 5 or 50?mg/kg over 2?h. At t=30?min after acute 50?mg/kg injection, respective plasma levels of ACY-738 and ACY-775 are 515?ng/mL (1.9?μM) and 1359?ng/mL (4.1?μM). Elimination from plasma is rapid, with plasmatic half-life of 12?min and concentration below 10?ng/mL after 2?h. Nevertheless, areas under concentration time curves for brain and plasm calculated over 2?h for both ACY-738 and ACY-775 lead to ratios >1. When ACY-738 (5?mg/kg) or ACY-775 (50?mg/kg) are administered repeatedly in wild-type mice at 24?h, 4?h, and 30?min before killing, significant increases in α-tubulin acetylation are observed in all tested brain regions.

ACY 775 | ACY775

Cell Cycle/DNA Damage

HDAC

HDAC

——

——

1375466-18-4

330.36

C17H19FN4O2

>98% (HPLC)

DMSO : 100 mg/mL 302.70 mM

O=C(C1=CN=C(NC2(C3=CC=CC(F)=C3)CCCCC2)N=C1)NO

2-((1-(3-fluorophenyl)cyclohexyl)amino)-N-hydroxypyrimidine-5-carboxamide

(-20℃)

With Ice Pack

≥ 2 years