BRL-50481

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.

Signaling Pathways >> Metabolic Enzyme/Protease >> Phosphodiesterase (PDE)

Research Areas >> Neurological Disease

IC50: 0.15 μM (PDE7A), 12 μM (PDE7B), 62 μM (PDE4), 490 μM (PDE3)[1]

BRL-50481 increases the cAMP content (19.1±6.2% of IBMX response at 300 μM) but is considerably less potent. 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)[2].

MOLT-4 cells in 96-well plates are treated for 30 min with BRL-50481 as indicated. The cAMP content is then determined by an immunospecific ELISA. Results are expressed as a percentage of the response affected by 100 μM IBMX[2].

[1]. Safavi M, et al. New methods for the discovery and synthesis of PDE7 inhibitors as new drugs for neurologicaland inflammatory disorders. Expert Opin Drug Discov. 2013 Jun;8(6):733-51.

[2]. Smith SJ, et al. Discovery of BRL 50481 [3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene], a selective inhibitor of phosphodiesterase 7: in vitro studies in human monocytes, lung macrophages, and CD8+ T-lymphocytes. Mol Pharmacol. 2004 Dec;66(6):1679-89.

3-Isobutyl-1-methylxanthine | rolipram | PF-04957325 | AN-2728 | GLPG1690 | BAY-60-7550 | Icariin | Ibudilast | PF-8380 | TAK-063 | Dipyridamole | Cilostazol | GSK256066 | Cialis | Pentoxifylline