Roflumilast 是一种口服的长效 4 型磷酸二酯酶抑制剂 (PDE4)，具有抗炎和潜在的抗肿瘤活性，作用于PDE4A1，PDEA4，PDEB1和PDEB2，IC50分别为 0.7，0.9，0.7 和 0.2 nM。

Roflumilast is an orally available, long-acting inhibitor of phosphodiesterase (PDE) type 4 (PDE4), with anti-inflammatory and potential antineoplastic activities. Upon administration, roflumilast and its active metabolite roflumilast N-oxide selectively and competitively bind to and inhibit PDE4, which leads to an increase of both intracellular levels of cyclic-3', 5'-adenosine monophosphate (cAMP) and cAMP-mediated signaling.

在体内实验中,Roflumilast使氧化压力下降.在动物模型中,Roflumilast可一定程度抵抗肺炎（COPD相关）.在暴露于烟草7个月的小鼠肺中, Roflumilast（5 mg/kg/day ）诱导巨噬细胞,中性粒细胞,B细胞,树突状细胞,CD8+ T细胞,CD4+ T 细胞分别减少82%,78%,100%, 48%,88%和98%.博来霉素气管内给药14天后,Roflumilast（5 mg/kg/day ）可适度降低小鼠BAL体液中过氧化氢脂质的增高.在博来霉素处理以后,Roflumilast剂量依赖性降低肺部总羟脯氨酸含量,5 mg/kg/day可抑制47%,并降低肺部纤维化损伤和αI(I)胶原蛋白转录.

在体外实验中,Roflumilast起免疫调节和抗炎活性作用。Rolfumilast对抗CD28和CD3抗体激活的CD4+ T细胞具有抑制作用（IC30：7 nM）,且分别对IL-2（IC20：1 nM）,IL-4（IC30：7 nM）,IL-5（IC25：13 nM）,以及 IFN-v（IC35：8 nM）的合成有抑制作用。在人类嗜中性粒细胞中,Roflumilast抑制LTB4合成（IC50：2 nM）。在酸性粒细胞和中性粒细胞中,Roflumilast对fMLP刺激的ROS形成有抑制作用,IC35 分别是7 nM和4 nM。在单核细胞中,Roflumilast对脂多糖诱导的TNF-α合成有抑制作用（IC40：21 nM）。在源于单核细胞的树突状细胞中,Roflumilast对脂多糖诱导的TNF-α合成有抑制效果（IC20： 5 nM）。

PDE activity is determined with some modifications. The assay mixture contain 50 mM Tris (pH 7.4), 5 mM MgCl2, 0.5 μM cAMP or cGMP, and [3H]cAMP or [3H]cGMP (about 30,000 cpm/assay), the indicated concentration of the inhibitor and an aliquot of the enzyme solution at a final assay volume of 200 μL. Stock solutions of the compounds are diluted 1:100 (v/v) in the Tris buffer mentioned above; appropriate dilutions are prepared in 1% (v/v) DMSO/Tris buffer, which are diluted 1:2 (v/v) in the assays to obtain the desired final concentrations of the inhibitors at a DMSO concentration of 0.5% (v/v). DMSO itself affected none of the PDE activities. After preincubation for 5 min at 37°C, the reaction is started by the addition of substrate (cAMP or cGMP) and the assays are incubated for further 15 min at 37°C. Then 50 μL of 0.2 N HCl is added to stop the reaction and the assays are left on ice for about 10 min. Following incubation with 25 μg of 5′-nucleotidase (Crotalus atrox snake venom) for 10 min at 37°C, the assays are loaded on QAE Sephadex A-25 (1 mL of bed volume in Poly-Prep chromatography columns). The columns are eluted with 2 mL of 30 mM ammonium formate (pH 6.0) and the eluate is counted for radioactivity. Results are corrected for blank values (measured in the presence of denatured protein) that are below 5% of total radioactivity. The amount of cyclic nucleotides hydrolyzed did not exceed 30% of the original substrate concentration[3].

162401-32-3

C17H14Cl2F2N2O3

403.21

B9302-107;BY 217;罗氟司特;APTA 2217;BYK 20869

Ethanol:12 mg/mL (29.8 mM)
DMSO:75 mg/mL (186 mM)
H2O:<1 mgml
Powder: -20°C for 3 years
In solvent: -80°C for 2 years