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Roflumilast

Basic information Indications and Usage Mechanisms of Action Pharmacokinetics Safety Related Supplier
Roflumilast Basic information
Roflumilast Chemical Properties
  • Melting point:158°C
  • Boiling point:430.6±45.0 °C(Predicted)
  • Density 1.471±0.06 g/cm3(Predicted)
  • storage temp. Refrigerator
  • solubility DMSO: soluble20mg/mL, clear
  • form powder
  • pka9.89±0.70(Predicted)
  • color white to beige
  • Merck 14,8249
  • CAS DataBase Reference162401-32-3(CAS DataBase Reference)
Safety Information
  • Hazard Codes Xi
  • Risk Statements 36/37/38
  • Safety Statements 26
  • WGK Germany 3
  • RTECS CV3325600
Roflumilast Usage And Synthesis
  • Indications and UsageRoflumilast is a selective oral phosphodiesterase-4 (PDE-4) inhibitor and a benzamide compound. It was developed by the German company Altana in 1993 and is the only oral PDE-4 inhibitor used to treat respiratory tract diseases approved for sale. Roflumilast is the first drug of its kind to target severe chronic obstructive pulmonary disease (COPD), and it is also the first oral anti-inflammation drug specifically developed for COPD patients. Its unique properties can help regulate COPD: when used in combination with bronchodilators to treat extremely severe COPD patients, roflumilast can has the advantage of further reducing symptoms and deterioration rate, thus making it the first drug that targets patients with recurring deteriorating phenotype-specific COPD and severe air flow obstruction related to chronic coughing and excess phlegm. Besides being a treatment for severe COPD, roflumilast can also be used to prevent and treat livestock respiratory tract diseases, excess mucosa bronchitis cough, asthmatic bronchitis, and acute bronchitis and air sacculitis accompanied by abnormal respiratory tract secretion.
  • Mechanisms of ActionRoflumilast selectively inhibits PDE4 to prevent the signal transduction for inflammatory reactions, and it then inhibits the damage on lung tissue caused by respiratory tract diseases such as COPD and asthma.
  • PharmacokineticsRoflumilast is taken orally and is metabolized by cytochrome oxidase P45(CYP)3A4 and CYP1A2 enzyme into N-oxide. Roflumilast N-oxide’s activity is only 2-3 times weaker than that of roflumilast, and it also has relatively high PDE-4 selectivity. 90% of PDE-4 inhibition in the body is achieved by roflumilast N-oxide, while the other 10% is achieved by the original drug. A daily 500ng oral dose of roflumilast for a healthy person will produce a free blood concentration of roflumilast N-oxide in 24 hours of about 1-2 nmol•L-1, and its serum protein binding rate is about 97%. Smoking has little impact on roflumilast’s pharmacokinetics. Roflumilast mostly affects inflammation cells related to asthma, including eosinophils, neutrophils, and mast cells. This drug can specifically affect a certain enzyme that participates in smooth muscle contraction, it can prevent cAMP decomposition, thus preventing the signal transduction for inflammatory reactions, and it is anti-inflammatory, giving it relatively good curative effects in clinically treating asthma and COPD. Roflumilast can also significantly extend the deterioration of respiratory symptoms while also dramatically increasing patients’ quality of life.
  • DescriptionRoflumilast is a selective, orally active PDE4 inhibitor thatwas approved in Germany in July 2010 as an add-on to bronchodilator treatment for maintenance therapy of severe chronic obstructive pulmonary disorder (COPD) associated with chronic bronchitis in adult patients with a history of frequent exacerbations .
    Roflumilast and its primary metabolite roflumilast N-oxide are potent and competitive inhibitors of PDE4 and are equipotent against PDE4A, B, andD but inactive against PDE4C and the other ten members of the PDE family (PDEs 1–3, 5–11). Despite its inhibition of PDE4D (IC50=0.80 nM, N-oxide IC50=2.0 nM), roflumilast shows the lowest incidence of nausea (3–5%) among the PDE4 inhibitors investigated in clinical trials.Anti-inflammatory effects of roflumilast have been demonstrated in preclinical cellular and animal models. Roflumilast is synthesized in four steps from 3-(cyclopropylmethoxy)-4-hydroxybenzaldehyde. The difluoromethyl ether is introduced by alkylation of the free phenolic group with chlorodifluoromethane and base. The aldehyde moiety is oxidized to the benzoic acid, which is then converted to an acid chloride and coupled with 3,5-dichloro-4-aminopyridine. Roflumilast is rapidly absorbed and metabolized to its active metabolite, roflumilast N-oxide. Metabolism is mediated by CYP3A4 and CYP1A2.
  • Chemical PropertiesCrystallin Solid
  • OriginatorBYK Gulden Lomberg Chemische Fabrik GmbH (Germany)
  • UsesSelective phosphodiesterase 4(PDE4) inhibitor. Antiasthmatic; in treatment of chronic obstructive pulmonary disease
  • UsesRoflumilast (Daxas) is a selective inhibitor of PDE4 with IC50 of 0.2-4.3 nM.
  • Usesophthalmic solution
  • UsesA selective inhibitor of phosphodiesterase 4
  • DefinitionChEBI: A benzamide obtained by formal condensation of the carboxy group of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid with the amino group of 3,5-dichloropyridin-4-amine. Used for treatment of bronchial asthma and chronic obstructive pulmonary disease
  • brand nameDaxas
  • Mechanism of actionRoflumilast is the more potent of the two drugs, and along with its active metabolite, roflumilast-N-oxide, it is nonselective in its inhibitory action on PDE4B and PDE4D. The PDE4B appears to be the most closely linked to anti-inflammatory effects, whereas the PDE4D receptor subtype is thought to be linked to nausea, possibly through a central effect. Roflumilast exhibits 80% oral bioavailability and has an elimination half-life of 10 hours, whereas the N-oxide has an elimination half-life of 20 hours and has shown no drug interactions. Clinical trials in patients with asthma or COPD are quite promising.
  • Pharmacokinetics Roflumilast is well absorbed on oral administration and has a half-life of 10 hours. Roflumilast is metabolized in the liver to its N-oxide derivative, which also is a PDE4 inhibitor, and it has a plasma half-life of 20 hours.
  • Clinical Use Roflumilast is currently undergoing clinical trials in Europe for use in the treatment of both asthma and COPD.
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