Protease-activated receptors are a family of G-protein-coupled receptors implicated in inflammation, cell differentiation and proliferation. AZ3451 is an inhibitor of wild-type protease-activated receptor 2 (PAR2) with an IC50 value of 23 nM. AZ3451 also showed inhibitory effect on PAR2s with a single-point mutation on N222Q, H227A, H227Q, D228A, D228N, H135Y, I327L, G157M, Y210L, and F154A with IC50 values of 12, 12, 25, 23, 4.3, 20, 32, 780, 570 and 370 nM, respectively. In 1321N1 cells overexpressing wild-type human PAR2, stimulation of 1321N1 with SLIGRL led to the phosphorylation of extracellular signal-regulated kinase (ERK), whereas the induction of ERK phosphorylation was completely inhibited by AZ3451 at the concentration of 10 μM. The IP-One HTRF assay in 1321N1 cells stably expressing human PAR2 showed that the IC50 value of AZ3451 was 23nM vs. SLIGRL. The FLIPR assay showed that the IC50 values of AZ3451 were 5.4 nM and 6.6 nM against SLIGRL and trypsin, respectively[1].
作用机制
AZ3451 is an antagonist of PAR2 that binds to a remote allosteric site outside the helical bundle of the receptor, preventing structural rearrangements required for receptor activation[1].
AZ3451 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HUVEC cells
10 μM
1 hour
To investigate the effect of AZ3451 on CHI3L1/PAR2 signaling in HUVEC cells, results showed AZ3451 attenuated AICAR-induced HUVEC tubule formation and upregulation of CHI3L1/PAR2.
Biomedicines. 2022 Apr 29;10(5):1028
rat chondrocytes
10 μM
48 h
AZ3451 suppressed IL-1β-induced inflammation response, cartilage degradation and premature senescence.
Aging (Albany NY). 2019 Dec 16;11(24):12532-12545
AZ3451 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Sprague Dawley rats
Hyperuricemia model
Intraperitoneal injection
1 mg/kg
Daily for 6 weeks
To evaluate the protective effect of AZ3451 on hyperuricemia-induced renal injury. Results showed that AZ3451 significantly attenuated tubular dilatation and tubulointerstitial inflammatory cell infiltration, reduced serum creatinine and BUN levels, and significantly decreased serum KIM-1 and NGAL levels.
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