Roflumilast

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Structural formula
Structure of roflumilast
General
Non-proprietary name Roflumilast
other names

N - (3,5-dichloropyrid-4-yl) -3-cyclopropylmethoxy-4-difluoromethoxybenzamide ( IUPAC )

Molecular formula C 17 H 14 Cl 2 F 2 N 2 O 3
External identifiers / databases
CAS number 162401-32-3
EC number 685-382-2
ECHA InfoCard 100.210.960
PubChem 449193
ChemSpider 395793
DrugBank DB01656
Wikidata Q693482
Drug information
ATC code

R03 DX07

Drug class

PDE-4 inhibitors

properties
Molar mass 403.21 g mol −1
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
07 - Warning

Caution

H and P phrases H: 315-319-335
P: ?
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Roflumilast is the first approved drug from the group of phosphodiesterase-4 inhibitors (PDE-4 inhibitors), which is used to treat chronic obstructive pulmonary disease (COPD).

Clinical information

application areas

Approved areas of application

Roflumilast can be used for long-term therapy in adult patients with severe COPD and chronic bronchitis as well as frequent worsening of the clinical picture (so-called exacerbations) in the past in addition to treatment with a bronchodilator drug. Severe COPD within the meaning of the approval of roflumilast shows a reduced one-second capacity (FEV 1 ) of less than 50% of the target value after the use of a bronchodilator drug.

Previous clinical studies have shown that the therapeutic window of PDE-4 inhibitors for use in respiratory diseases is limited due to dose-limiting side effects such as nausea , diarrhea and headache . If the active ingredient was not very effective against COPD and asthma, these studies showed side effects in the gastrointestinal area. Possible further weight loss is particularly critical in underweight patients with COPD. The cost-effectiveness analysis came to the result that roflumilast would increase the treatment costs for COPD, but that consequential costs in the further treatment of the patients could be saved.

Further possible areas of application

The active ingredient has also been studied for the treatment of bronchial asthma . However, the results of these investigations have not yet been published. According to the manufacturer, roflumilast was in development phase I in 2008 for the application areas of atopic dermatitis and psoriasis .

Other Information

Chemical and pharmaceutical information

The following synthetic route was described in a patent issued in 1998:

synthesis

History

The pharmaceutical division of Altana (formerly Byk Gulden ), which Nycomed acquired in 2006 , had already submitted roflumilast for approval for COPD in the EU in 2004 , but withdrew the application in 2005 after consultation with the European Medicines Agency . Shortly beforehand, Altana's development partner Pfizer had ended the collaboration with Altana.

In 2009, Nycomed submitted the application again in the EU based on positive results in four new clinical studies. In 2010, the European Commission granted Nycomed EU approval for roflumilast. In 2011 the manufacturer also received approval in the USA . A decision for Switzerland is still pending. The patent protection for roflumilast expired in 2014.

In December 2015, AstraZeneca announced that it would take over the worldwide marketing rights for roflumilast.

Trade names

literature

  • A. Hatzelmann, C. Schudt: Anti-inflammatory and Immunomodulatory Potential of the Novel PDE4 Inhibitor Roflumilast in Vitro . Journal of Pharmacology and Experimental Therapeutics , 297, 267-279 (2001)
  • BM Gensthaler: PDE-4 inhibitors against COPD and asthma . Pharmaceutical newspaper 14 (2003)
  • SA Antoniu: New therapeutic options in the management of COPD - focus on roflumilast. In: International journal of chronic obstructive pulmonary disease. Volume 6, 2011, pp. 147-155, doi : 10.2147 / COPD.S7336 . PMID 21468165 . PMC 3064419 (free full text).

Individual evidence

  1. ↑ Template: CL Inventory / not harmonized There is not yet a harmonized classification for this substance . A labeling of 3- (cyclopropylmethoxy) -N- (3,5-dichloropyridin-4-yl) -4- (difluoromethoxy) benzamide in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA) is reproduced, which is derived from a self-classification by the distributor on July 12, 2020.
  2. ↑ a b Summary of the European Public Assessment Report (EPAR) for Daxas (PDF; 126 kB) European Medicines Agency . P. 3. Accessed December 16, 2015.
  3. ↑ a b AstraZeneca to strengthen therapy area franchise through acquisition of Takeda's respiratory business , PM AstraZeneca of December 16, 2015, accessed on December 16, 2015
  4. ↑ Spina D. PDE4 inhibitors: current status. British Journal of Pharmacology . (2008) 155, 308-315, PMID 18660825 .
  5. ↑ Giembycz MA. Can the anti-inflammatory potential of PDE4 inhibitors be realized: guarded optimism or wishful thinking? British Journal of Pharmacology . (2008) 155, 288-290, PMID 18660832 .
  6. ↑ NN. Roflumilast - a new drug for COPD. (PDF; 98 kB) special report 7/2009, p. 11. Ars Medici. 2009; Volume 99.
  7. ^ Field SK. Roflumilast: an oral, once-daily selective PDE-4 inhibitor for the management of COPD and asthma. Expert Opinion on Investigational Drugs . 2008 May; 17 (5): 811-818, PMID 18447606 .
  8. ^ Nycomed GmbH: Research pipeline . ( Memento of September 28, 2008 in the Internet Archive ) Accessed August 15, 2008.
  9. ↑ Patent US5712298 : Fluoroalkoxy-substituted benzamides and their use as cyclic nucleotide phosphodiesterase inhibitors. Published on January 27, 1998 , inventor: Hermann Amschler. ‌
  10. ^ Altana AG: Press release of February 13, 2004. Accessed on August 15, 2008.
  11. ^ Altana AG: Press release from November 15, 2005. Accessed August 15, 2008.
  12. ^ Altana AG: Press release from July 1, 2005. Accessed August 15, 2008.
  13. ↑ Nycomed GmbH: Nycomed applies for European marketing authorization for Daxas® for the treatment of COPD , press release of May 8, 2009.
  14. ↑ US Food and Drug Administration (March 1, 2011): FDA approves new drug to treat chronic obstructive pulmonary disease. Accessed May 20, 2011.
  15. ^ Gerson Lehrman Group (May 12, 2009): Nycomed's Daxas takes an important step forward. Accessed July 21, 2009.

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