Roflumilast
Daliresp · Daxas · BY 217 · Roster · CS-1960 · Roflost · BYK 20869 · APTA 2217
Identifikatoren & physikalische Daten
| CAS No. | 162401-32-3 |
|---|---|
| Summenformel | C17H14Cl2F2N2O3 |
| Durchschnittliche Molmasse | 403,2 g/mol |
| Monoisotopische Masse | 402,03495411 g/mol |
| SMILES | O=C(Nc1c(Cl)cncc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1 |
| InChIKey | MNDBXUUTURYVHR-UHFFFAOYSA-N |
| PubChem CID | 449193 |
| ChEMBL | CHEMBL193240 |
| ChEBI | CHEBI:47657 |
| EC No. | 685-382-2 |
| DTXSID | DTXSID8044123 |
Chemische & physikalische Eigenschaften
| XLogP | 4,6 |
|---|---|
| Polarare Oberfläche (TPSA) | 60,5 |
| H-Brücken-Donoren | 1 |
| H-Brücken-Akzeptoren | 6 |
| Frei drehbare Bindungen | 7 |
| Schwere Atome | 26 |
| Formalladung | 0 |
| Komplexität | 475 |
| Arzneimittel | Pharmaceuticals -> Listed in ZINC15Pharmaceuticals -> Respiratory system -> Nasal preparations |
| Löslichkeit | Sparingly solubleDMSO: soluble20mg/mL, clear |
| Human Drugs | Breast FeedingLactationMilk, HumanPhosphodiesterase 4 InhibitorsFDA approved drugs -> Active ingredientEMA approved medicines: Human medicine |
| Dissociation Constants | 8.74 |
| Schmelzpunkt | 158°C |
| Siedepunkt | 430.6±45.0 °C(Predicted) |
| Dichte | 1.471±0.06 g/cm3(Predicted) |
| Lagerbedingungen | -20°C |
| pKa (Säurekonstante) | 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 & Vorschriften
| GHS-Einstufung | WarningH315 (91.1%): Causes skin irritation [Warning Skin corrosion/irritation]P261, P264, P264+P265, P271, P280, P302+P352, P304+P340, P305+P351+P338, P319, P321, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 45 reports by companies from 8 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies. |
|---|---|
| Hazard Classes and Categories | Skin Irrit. 2 (91.1%) |
| Hepatotoxicity | In preregistration studies, roflumilast was not associated with serum enzyme elevations or with episodes of clinically apparent liver injury. Since approval of roflumilast, there have been no published reports of hepatotoxicity, and the product label does not mention liver injury as an adverse event. |
| Drug Induced Liver Injury | Drug Induced Liver Injury Rank (DILIrank 2.0)RoflumilastvNo-DILI-concernNo matchDOI:10.1016/j.drudis.2016.02.015 |
| Effects During Pregnancy and Lactation | ◉ Summary of Use during Lactation |
| Wassergefährdungsklasse (WGK) | 3 |
| Zollcode | 2933.39.4100 |
| RTECS-Nr. | CV3325600 |
| R-Sätze (R) | 36/37/38 |
| Gefahrensymbole | Xi |
| Sicherheitshinweise (S) | 26 |
| Lagerklasse | 11 - Combustible Solids |
| Gefahrenklasse | Eye Irrit. 2Skin Irrit. 2STOT SE 3 |
Anwendungen & Verwendung
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.
Verwenden
Roflumilast (Daxas) is a selective inhibitor of PDE4 with IC50 of 0.2-4.3 nM.