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. IC50 & Target: IC50: 0.15 μM (PDE7A), 12 μM (PDE7B), 62 μM (PDE4), 490 μM (PDE3)^[1] In Vitro: 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].