Roflumilast

Bezeichnung:Roflumilast

CAS-Nr162401-32-3

Englisch Name:Roflumilast

CBNumberCB7412688

SummenformelC17H14Cl2F2N2O3

Molgewicht403.21

MOL-Datei162401-32-3.mol

Roflumilast physikalisch-chemischer Eigenschaften

Schmelzpunkt	158°C
Siedepunkt	430.6±45.0 °C(Predicted)
Dichte	1.471±0.06 g/cm3(Predicted)
storage temp.	-20°C
Löslichkeit	DMSO: soluble20mg/mL, clear
pka	9.89±0.70(Predicted)
Aggregatzustand	powder
Farbe	white to beige
Merck	14,8249
Stabilität	Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
InChI	InChI=1S/C17H14Cl2F2N2O3/c18-11-6-22-7-12(19)15(11)23-16(24)10-3-4-13(26-17(20)21)14(5-10)25-8-9-1-2-9/h3-7,9,17H,1-2,8H2,(H,22,23,24)
InChIKey	MNDBXUUTURYVHR-UHFFFAOYSA-N
SMILES	C(NC1C(Cl)=CN=CC=1Cl)(=O)C1=CC=C(OC(F)F)C(OCC2CC2)=C1
CAS Datenbank	162401-32-3(CAS DataBase Reference)

Sicherheit

Kennzeichnung gefährlicher	Xi
R-Sätze:	36/37/38
S-Sätze:	26
WGK Germany	3
RTECS-Nr.	CV3325600
HS Code	2933.39.4100

Gefahreninformationscode (GHS)

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 (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.
Beschreibung
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 (IC₅₀ = < 1 nM for both human PDE4B and PDE4D). It is selective for PDE4, with IC₅₀ 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.
Chemische Eigenschaften
Crystallin Solid
Originator
BYK Gulden Lomberg Chemische Fabrik GmbH (Germany)
Verwenden
Selective phosphodiesterase 4(PDE4) inhibitor. Antiasthmatic; in treatment of chronic obstructive pulmonary disease
Verwenden
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.
Verwenden
Roflumilast (Daxas) is a selective inhibitor of PDE4 with IC50 of 0.2-4.3 nM.
Verwenden
ophthalmic solution
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
Trademarks
Daxas
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.
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.
Synthese
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
Lager
Store at +4°C
Einzelnachweise
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

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