BRL-50481 is a novel and selective inhibitor of PDE7 with IC50s of 0.15, 12.1, 62 and 490 μM for PDE7A, PDE7B, PDE4 and PDE3, respectively. BRL-50481 (30 μM) fails to suppress proliferation by itself but significantly potentiates the effect of rolipram. BRL-50481 (30 μM) has no effect on IL-15-induced proliferation but augments the inhibitory effect of rolipram. Pretreatment (30 min) of human monocytes with BRL-50481 has, by itself, a negligible (~2 to 10%) inhibitory effect on TNFα output at all concentrations tested. BRL-50481 also potentiates the inhibitory effect of PGE2 on LPS-induced TNFα release. BRL-50481 has no significant effect by itself on κB-dependent transcription (5.6±1.9% inhibition at 30 μM) and fails to enhance the effect of rolipram (maximum inhibition, 52.9±2.7%; pIC30 value of 5.33±0.12). BRL-50481 suppresses, in a concentration-dependent manner, LPS-induced TNFα release in monocytes in which PDE7A1 is induced (21.7±1.6% inhibition at 30 μM at the 12-h time point)[1].
BRL-50481 细胞实验
Cell Line
Concentration
Treated Time
Description
References
rat aortic smooth muscle cells (RASMCs)
50 μM
3 min
To evaluate the role of PDE7 in regulating cAMP signals, results showed BRL had minor effects on the kinetics of Iso-induced FRET signal (time to peak increased by 17%)
PLoS One. 2012;7(10):e47826
OPCs isolated from adult human brain biopsies
1 μM
5 days
To investigate the effects of PDE7 inhibitors on human OPC differentiation, results showed that VP1.15 and TC3.6 significantly promoted OPC differentiation into oligodendrocytes.
Cell Mol Life Sci. 2013 Sep;70(18):3449-62
EHEB cells
30 µM
48 h
Assess the effect of BRL-50481 on proliferation of EHEB cells; results show it inhibits proliferation by 19±1%.
Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19532-7
CLL cells
30 µM
48 h
Evaluate the effect of PDE7 inhibitors on apoptosis of CLL cells; results show BRL-50481 significantly induces apoptosis in CLL cells.
Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19532-7
BRL-50481 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Male BALB/c mice
ConA-induced autoimmune hepatitis model
Intraperitoneal injection
50 mg/kg
Single dose, hepatitis induced 30 minutes later
To evaluate the anti-inflammatory and hepatoprotective effects of BRL-50481 in the ConA-induced hepatitis model. Results showed that BRL-50481 significantly reduced serum TNF-α and IL-17 levels and alleviated liver injury.
J Pharmacol Exp Ther. 2022 May;381(2):151-163
SJL mice
Experimental autoimmune encephalomyelitis (EAE)
Intraperitoneal injection
10 μg/g body weight
Daily administration, starting from the day of MBP inoculation (D0)
Evaluate the therapeutic effect of BRL50481 on EAE, results showed BRL50481 had no effect on the disease course
Br J Pharmacol. 2013 Oct;170(3):602-13
C57BL/6J mice
Partial sciatic nerve ligation (PSNL) and complete Freund’s adjuvant (CFA) induced chronic pain and depression models
Oral
10 mg/kg
Once daily for 14-33 days
BRL50481 significantly alleviated PSNL- or CFA-induced mechanical hypersensitivity and depression-like behavior and reversed the downregulation of cAMP-PKA-CREB-BDNF signaling and increased neuroinflammation in the hippocampus.
Int J Neuropsychopharmacol. 2024 Oct 1;27(10):pyae040
BALB/c mice
OVA-induced asthmatic lung inflammation model
Intraperitoneal injection
2 mg/kg
Administered 1 hour before each challenge, total of 6 times
BRL significantly reduced AHR, infiltration of inflammatory cells, Th2-related cytokines, antigen-specific immunoglobulins, and mucin levels, ameliorating OVA-induced allergic asthmatic responses.
搜索
