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Roflumilast

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Chemical Structure| 162401-32-3 同义名 : APTA-2217;BYK 20869;Daliresp;Daxas;BY 217;B9302-107
CAS号 : 162401-32-3
货号 : A168666
分子式 : C17H14Cl2F2N2O3
纯度 : 99%
分子量 : 403.21
MDL号 : MFCD00938270
存储条件：

粉末 Inert atmosphere,Store in freezer, under -20°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 50 mg/mL(124 mM)，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：
生物活性
靶点

  • PDE4

    PDE4A4, IC50:4.3 nM

    PDE4A1, IC50:0.7 nM
描述 Phosphodiesterases (PDEs) are a family of enzymes that catalyze the hydrolysis of cyclic adenosine monophosphate and cyclic guanosine monophosphate. Roflumilast is a potent inhibitor of both human PDE4B and PDE4D with IC50 values of 0.84 and 0.68nM, respectively, while it showed much less inhibitory activity against other forms of PDEs (IC50 values > 10μM)[7]. In A549 cells, roflumilast at the dose of 1μM prevented EGF-stimulated increase in MUC5AC mRNA and protein production but did not change the basal MUC5AC expression, and also inhibited EGF-induced phosphorylation of tyrosine residues of different intracellular proteins (i.e. EGF receptor, phospho-p38- and p44/42-MAPK) and the upregulation of EGFR expression. In human isolated bronchus, the presence of 1μM roflumilast inhibited EGF-induced MUC5AC mRNA and protein expression[8]. In A/J mice expressing wild type cystic fibrosis transmembrane conductance regulator (CFTR) and exposed to cigarette smoke or air, acute roflumilast (30nM) treatment increased CFTR-dependent chloride transport in both smoke- and air-exposed mice as compared to vehicle-treated group. Oral administration of roflumilast (5mg/kg/day, once per day) for five weeks activated CFTR and completely reversed cigarette smoke-induced adverse effects in vivo[9].
作用机制 The difluromethoxy group of roflumilast binds at the Q1 pocket of enzyme, while the cyclopropyl methoxy group binds at the Q2 pocket[7].
细胞研究
细胞系 浓度 检测类型 检测时间 活动说明 数据源
HEK293 cells Function assay 15 min Inhibition of PDE4 expressed in HEK293 cells coexpressing cyclic nucleotide gated ion channel mutant assessed as inhibition of NECA-induced cAMP production treated 15 mins before NECA challenge measured after 45 mins by FLIPR assay 20378348
PBMC Function assay Inhibition of TNFalpha production in LPS-stimulated human PBMC preincubated before LPS challenge measured after 4 hrs by enzyme immunoassay, IC50=2e-05 μM 19256507
sf21 cells Function assay Inhibition of human full length PDE4A4 expressed in baculovirus infected sf21 cells, IC50=0.35 nM 23806553
临床研究
NCT号 适应症或疾病 临床期 招募状态 预计完成时间 地点
NCT03762330 Chronic Obstructive Pulmonary ... 展开 >>Disease 收起 << Not Applicable Not yet recruiting January 2021 -
NCT02835716 - Recruiting September 2020 United States, Connecticut ... 展开 >> Millennium Magnetic Technologies, LLC Recruiting Westport, Connecticut, United States, 06880 Contact: Steve Levy, MD    203-423-9494    SL@MilMag.net    Contact: Donald H Marks, MD PhD    9733070364    DHM@MilMag.net 收起 <<
NCT01730404 COPD Phase 2 Completed - Ireland ... 展开 >> Celerion Belfast, Ireland United Kingdom Parexel, early phases Harrow, United Kingdom Medicines Evaluation Unit Ltd Manchester, United Kingdom Freeman Hospital Newcastle, United Kingdom Nottingham University Hospitals NHS Trust Nottingham, United Kingdom 收起 <<
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.48mL

0.50mL

0.25mL

12.40mL

2.48mL

1.24mL

24.80mL

4.96mL

2.48mL
参考文献

[1]Martorana PA, Lunghi B, et al. Effect of roflumilast on inflammatory cells in the lungs of cigarette smoke-exposed mice. BMC Pulm Med. 2008 Aug 28;8:17.

[2]Hatzelmann A, Schudt C. Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J Pharmacol Exp Ther. 2001 Apr;297(1):267-79.

[3]Wollin L, Marx D, et al. Roflumilast inhibition of pulmonary leukotriene production and bronchoconstriction in ovalbumin-sensitized and -challenged Guinea pigs. J Asthma. 2005 Dec;42(10):873-8.

[4]Martorana PA, Beume R, et al. Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke. Am J Respir Crit Care Med. 2005 Oct 1;172(7):848-53. Epub 2005 Jun 16.

[5]Kasetty G, Papareddy P, et al. Roflumilast Increases Bacterial Load and Dissemination in a Model of Pseudomononas Aeruginosa Airway Infection. J Pharmacol Exp Ther. 2016 Apr;357(1):66-72.

[6]Roflumilast

[7]Card GL, England BP, Suzuki Y, Fong D, Powell B, Lee B, Luu C, Tabrizizad M, Gillette S, Ibrahim PN, Artis DR, Bollag G, Milburn MV, Kim SH, Schlessinger J, Zhang KY. Structural basis for the activity of drugs that inhibit phosphodiesterases. Structure. 2004 Dec;12(12):2233-47.

[8]Mata M, Sarriá B, Buenestado A, Cortijo J, Cerdá M, Morcillo EJ. Phosphodiesterase 4 inhibition decreases MUC5AC expression induced by epidermal growth factor in human airway epithelial cells. Thorax. 2005 Feb;60(2):144-52.

[9]Raju SV, Rasmussen L, Sloane PA, Tang LP, Libby EF, Rowe SM. Roflumilast reverses CFTR-mediated ion transport dysfunction in cigarette smoke-exposed mice. Respir Res. 2017 Sep 18;18(1):173.