PDE4B is an enzyme that in humans is encoded by the PDE4B gene. Importantly, PDE4B is involved in dopamine-associated and stress-related behaviors. Particularly, study show that reduction in PDE4B activity improves memory and long-term plasticity in mouse models. Besides, PDE4B regulates both L-type calcium channels and the ryanodine receptor, which controls the process of calcium-induced calcium release. In addition, PDE4 shows activity in regulating inflammation and the modulation of immunocompetent cells. So, PDE4 inhibitors currently available support a beneficial role for PDE4 inhibitors in inflammatory and/or autoimmune diseases.
In this article, we will introduce a potent and orally active inhibitor of PDE4B, BI 1015550.
BI 1015550 is an orally active inhibitor of PDE4B with an IC50 value of 7.2 nM. Besides, BI 1015550 inhibits Lipopolysaccharides induced TNF-α release and Phytohemagglutinin P induced IL-2 release in human PBMCs with IC50 values of 35 nM and 9 nM, respectively. Moreover, This compound inhibits TNF-α release in rat whole blood with an IC50 value of 91 nM.
BI 1015550 (0, 0.3, 1.0 and 3.0 mg/kg; p.o.; single dose) weakens intestinal transport in rats at 1.0 mg/kg without significantly affecting body weight. Additionally, BI 1015550 prevents inflammation in rat lung tissue with an ED50 value of 0.1 mg/kg. Furthermore, BI 1015550 (0.01, 0.1 and 1.0 mg/kg; p.o.; single dose) reduces the Lipopolysaccharides induced TNF-α release in dose-dependent manner in mice plasma. Meanwhile, BI 1015550 (0.1, 0.3 and 1.0 mg/kg; p.o.; single dose) inhibits lipopolysaccharides-induced neutrophil entry into bronchoalveolar lavage fluid of male Suncus murinus and Wistar rats. What’s more, BI 1015550 (2.5 mg/kg and 12.5 mg/kg; p.o.; twice daily for 6 days) effectively improves the damage of Bleomycin to mice.
All in all, BI 1015550 is an orally active inhibitor of PDE4B and shows good safety and potential applications in inflammation, allergic diseases, pulmonary fibrosis, and chronic obstructive pulmonary disease (COPD).