Indications and Usage
Roflumilast(162401-32-3) 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 Action
Roflumilast 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.
Pharmacokinetics
Roflumilast(162401-32-3) 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.
Description
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.
Description
Type 4 cyclic nucleotide phosphodiesterase (PDE4) isoforms selectively inactivate the second messenger cAMP by hydrolyzing the phosphodiester bond, producing AMP. Roflumilast is a potent, cell-
permeable inhibitor of PDE4 (IC
50 = < 1 nM for both human PDE4B and PDE4D). It is selective for PDE4, with IC
50 values against other PDE forms being greater than 10 μM. Roflumilast demonstrates good bioavailability and has applications in respiratory diseases, including asthma and chronic obstructive pulmonary disease.
Chemical Properties
Crystallin Solid
Originator
BYK Gulden Lomberg Chemische Fabrik GmbH (Germany)
Uses
Selective phosphodiesterase 4(PDE4) inhibitor. Antiasthmatic; in treatment of chronic obstructive pulmonary disease
Uses
Roflumilast is a selective, long-acting PDE-4 inhibitor approved in 2010 for the treatment of
inflammatory conditions of the lungs such as asthma and chronic obstructive pulmonary disorder. Marketed under the trade name Daxas?, roflumilast was developed by researchers at the
University of Liverpool in partnership with Nycomed. Although the dose-limiting side effects of the
drug are mild nausea, diarrhea, and weight loss, these symptoms subsided after a few weeks of
treatment.
Uses
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
Biochem/physiol Actions
Roflumilast is a highly potent, orally active, and selective phosphodiesterase 4 (PDE4) inhibitor with an IC50 of 0.8 nM. Roflumilast has anti-inflammatory properties and is used clinically to treat COPD.
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.
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.
Side effects
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.
Synthesis
The straightforward preparation of roflumilast begins with commercially available
methyl 3,4-dihydroxybenzoate (130). Alkylation of the more reactive 3-
hydroxyl group with (bromomethyl)cyclopropane (131) preceded a second alkylation of the remaining
p-phenol with chlorodifluoromethane in aqueous sodium hydroxide. These phase-transfer conditions
saponified the ester within 130 and after acidic quench, carboxylic acid 132 was ultimately furnished in
excellent yield (97%) over the three step protocol. Activation of 132 as the corresponding acyl halide
through use of thionyl chloride (SOCl2) and subsequent exposure to commercial aminopyridine 133
provided roflumilast (XII) in 81% yield.
target
cAMP | ROS | IL Receptor | PDE
References
1) Hatzelmann?et al.?(2010),?The preclinical pharmacology of roflumilast—a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease; Pulm, Pharmacol. Ther.,?23?235
2) Rabe?et al.?(2011),?Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease; Br. J. Pharmacol,?163?53
3) Heckman?et al.?(2018),?Acute administration of roflumilast enhances sensory gating in healthy young humans in a randomized trial; Psychopharmacology (Berl.),?235?301
4) Vanmierlo?et al.?(2016),?The PDE4 inhibitor roflumilast improves memory in rodents at non-emetic doses;?Behav. Brain Res.,?303?26
5) Tikoo?et al.?(2014),?Calorie restriction mimicking effects of roflumilast prevents diabetic nephropathy; Biochem. Biophy. Res. Commun.,?450?1581
6) Mollmann?et al.?(2017),?The PDE4 inhibitor roflumilast reduced weight gain by increasing energy expenditure and leads to improved glucose metabolism; Diabetes Obes. Metab.,?19?496
