|Roflumilast Chemical Properties|
|Roflumilast Usage And Synthesis|
|Physical and chemical properties||White to light tan solid particles or crystalline powder. Odorless, slightly sweet taste, and soluble in water.|
|Phosphodiesterase 4 (PDE4) inhibitors||Roflumilast is a kind of oral and selective phosphodiesterase IV (PDE4) inhibitors. It is benzamides compound. And it is the only approved oral phosphatase IV (PDE-4) inhibitors that used in the treatment of respiratory diseases currently. It can selectively inhibit PDE4, block the signal transduction of inflammation, and then inhibit the damage to lung tissue caused by respiratory diseases such as COPD and asthma. It has proven to be a new mode of action in inhibiting COPD related-inflammation. Roflumilast is a once-daily tablet, and the first new type of drug for the treatment of severe COPD. It is also the first oral anti-inflammatory drugs for patients with COPD. Its unique nature can facilitate the better management of chronic obstructive pulmonary patients: when the combination with bronchodilator in the treatment of the most severe chronic obstructive pulmonary patients, roflumilast can offer the additional benefits of further reducing the symptoms and disease progression rates. Then it became the first drug of targeting particular phenotype of chronic obstructive pulmonary disease that is patients with severe airflow limitation and having a history of recurrent disease worsening associated with chronic cough and sputum.|
In 1993, Germany Altana Company successfully developed roflumilast for the first time. It is already the products of Switzerland Nycomed Pharmaceutical GmbH. In 2009, the company completed phase III clinical trials of roflumilast and submitted a listing application in Europe. The European Union approved the roflumilast (Daxas) to the market on July 6, 2010. Then Nycomed signed a cooperation agreement with Forest Lab. Forest Lab invested $600 million to obtain the rights to sell daxas in the US, and it was responsible for the application of roflumilast in the FDA and roflumilast’s promotion and sale. While Nycomed will retain the right to sell the drug in Europe and other regions of the world.
The above information is edited by the Chemicalbook of Ge Qian.
|Indications||Roflumilast can be used for the prevention and treatment of respiratory disease, and used for the treatment of severe chronic obstructive pulmonary disease (COPD) and excessive mucus cough bronchitis, asthmatic bronchitis, bronchial asthma, respiratory tract associated with abnormal secretion of acute and chronic bronchitis, air sacculitis, etc. |
Chronic obstructive pulmonary disease (referred to as "COPD"), is chronic lung disease that characterized by incompletely reversible airflow obstruction. It is usually manifested clinically recurrent cough, sputum, dyspnea and other symptoms. That usually shows progressive progress features, including the vast majority of chronic bronchitis and emphysema. As the disease progresses, it will lead to airway remodeling, and ultimately develop to irreversible airflow obstruction, or coexist with asthma overlap. Therefore, improving the control of airflow obstruction and inflammation is the main goal of drug research at home and abroad.
Chronic obstructive pulmonary disease (COPD) is one of progressive and life-threatening lung disease and one of the human health "killer". It makes dyspnea, loss of activity. The disease typically includes chronic bronchitis and emphysema. It is estimated that about 210 million people worldwide suffer from the disease, and COPD will become the third largest cause of death in the world by 2020. Based on the conclusions of the US National Heart, Lung, and Blood Institute, smoking is the major risk factor for COPD.
|Pharmacokinetics||Roflumilast is taken orally. When roflumilast enter into the body, n-oxide is generated by cytochrome oxidase P450(CYP)3A4 and CYP1A2 enzyme metabolism. The activity of roflumilast n-oxide is only two to three times weaker than roflumilast. It also has a high selectivity of PDE-4. The inhibition of about 90% of PDE-4 is produced by roflumilast n-oxide in the human body. Another 10% is produced by roflumilast prototype. Healthy people takes 500μg roflumilast orally (one time a day). After 24h, the free plasma concentrations of roflumilast N- oxide is about 1~2nmol·L-1. The plasma protein binding is approximately 97%. The effect of smoking on roflumilast pharmacokinetics is less.|
Roflumilast is mainly act on asthma-related inflammatory cells, including eosinophils, neutrophils and mast cells. The drug can specifically act on an enzyme that involved in smooth muscle contraction, and can prevent the degradation of cAMP so that block the signaling of proinflammatory. It has anti-inflammatory activity and obtains a better effect in the clinical treatment of asthma and chronic obstructive pulmonary disease. Roflumilast also significantly delay the progression of respiratory symptoms. Meanwhile the quality of patients’ life can be greatly improved.
|Dosage||Roflumilast is oral tablet for daily once. It should be used with other bronchodilators. It is suitable for adult patients with a history of frequent exacerbation of chronic bronchitis and related severe COPD. And it can be used as maintenance therapy.|
The indications are: severe COPD patients with cough and phlegm that associated with bronchitis.
The treatment guidelines of roflumilast approved by the US Food and Drug Administration (FDA) shows that its potential menal health risks include changes of mood, thinking or behavior and unexplained weight loss. Roflumilast is not expected to use in other symptoms of COPD, including emphysema treatment. Roflumilast cannot be used in the treatment of sudden breathing problems (acute bronchospasm), and it is not recommended for patients 18 years of age. Major adverse events that are reported include diarrhea, nausea, headache, insomnia, back pain, poor appetite and dizziness.
|Patents||The patent documents of roflumilast compounds include IN2004MU00478, WO2005026095, WO2004033430, US6822114.|
In China, the patent documents of roflumilast is "fluoroalkoxy-substituted benzamides and their preparation methods and applications" (WO09501338, CN94192659). The patent was applied on July 2, 1994, and authorized on December 1, 1999. The patent protects the compound, preparation method and the application in the treatment of airway diseases or skin diseases. The patent expired on July 2, 2014.
|Chemical Properties||Crystallin Solid|
|Usage||Selective phosphodiesterase 4(PDE4) inhibitor. Antiasthmatic; in treatment of chronic obstructive pulmonary disease|
|Usage||Roflumilast (Daxas) is a selective inhibitor of PDE4 with IC50 of 0.2-4.3 nM.|
|Usage||A selective inhibitor of phosphodiesterase 4|
|Definition||ChEBI: 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|
|Roflumilast Preparation Products And Raw materials|