Roflumilast Chemische Eigenschaften,Einsatz,Produktion Methoden
Beschreibung
Roflumilast 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 (IC
50=0.80 nM, N-oxide
IC
50=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.
Chemische Eigenschaften
Crystallin Solid
Verwenden
Roflumilast (Daxas) is a selective inhibitor of PDE4 with IC50 of 0.2-4.3 nM.
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
Mechanism of action
Roflumilast 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.
Pharmakokinetik
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.
Nebenwirkungen
Common side effects of Roflumilast include: diarrhoea, nausea, dizziness, headache, back pain, muscle cramps, loss of appetite and weight loss. Severe can lead to persistent diarrhoea, acute pancreatitis, significant weight loss and psychiatric symptoms (such as anxiety, depression, insomnia and suicidal tendencies). In addition, the incidence of prostate, lung and colorectal cancer is significantly higher.
Roflumilast Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Downstream Produkte
