tcsc0963 Roflumilast

Roflumilast is a selective PDE4 inhibitor with IC₅₀s of 0.7, 0.9, 0.7, and 0.2 nM for PDE4A1, PDEA4, PDEB1, and PDEB2, respectively, without affecting PDE1, PDE2, PDE3 or PDE5 isoenzymes from various cells.

IC50 & Target: IC50: 0.7 nM (PDE4A1), 0.9 nM (PDE4A4), 0.7 nM (PDE4B1), 0.2 nM (PDE4B2)^[1]

In Vitro: Roflumilast does not affect PDE enzymes apart from PDE4, and is a subnanomolar inhibitor of most PDE4 splicing variants tested. It showed no PDE4 subtype selectivity apart from PDE4C (4C1, IC₅₀=3 nM; 4C2, IC₅₀=4.3 nM), which is inhibited with a slightly lower potency^[2]. Roflumilast is a potent and selective PDE4 inhibitor. Roflumilast is a monoselective PDE4 inhibitor since it does not affect other PDE isoenzymes, including PDE1, PDE2, PDE3, and PDE5 up to 10,000-fold higher concentrations. Roflumilast inhibits human neutrophil functions. Roflumilast inhibits TNFα synthesis in monocyte-derived dendritic cells. Rolfumilast inhibits proliferation and cytokine synthesis in CD4⁺ T cells. Proliferation is inhibited to a maximum of about 60% by Roflumilast with a potency (IC₃₀) of 7 nM^[3].

In Vivo: Animal studies with Roflumilast demonstrated that it reduced the accumulation of neutrophils in bronchoalveolar lavage fluid following short-term exposure of guinea pigs, mice or rats to tobacco smoke, and following exposure of rats to a combination of tobacco smoke and bacterial lipopolysaccharide, and abolished the lung parenchymal influx of inflammatory cells seen in rats exposed to tobacco smoke for 7 months^[2]. Roflumilast blocks COPD progression in pIgR^−/− mice. For these studies, 9-month-old WT or pIgR^−/− mice are treated daily by oral gavage with 100 μg of Roflumilast (5 μg/g) or vehicle (4% methylcellulose, 1.3% PEG400) for 3 months and lungs are harvested at 12 months of age. Unlike pIgR^−/− mice treated with vehicle, mice treated with Roflumilast had no progression of small airway wall remodelling after starting treatment. Strikingly, 12-month-old pIgR^−/− mice treated with Roflumilast had reduced indices of emphysema compared with 9-month-old pIgR^−/− mice, indicating that Roflumilast not only blocks progression of emphysema in this model but apparently facilitates some resolution of the emphysematous destruction of lung parenchyma^[4].