Roflumilast

Category	Respiratory syncytial Virus (RSV)
CAS	162401-32-3
Description	Roflumilast has anti-inflammatory effects and is under development as an orally administered drug for the treatment of inflammatory conditions of the lungs such as asthma, and chronic obstructive pulmonary disease (COPD). While Roflumilast was found to be effective in clinical trials, it produced several dose-limiting side effects including nausea, diarrhoea and headache, and development is continuing in an attempt to minimise the incidence of side effects while retaining clinical efficacy.

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Product Information

Synonyms	BY217; BY-217; BY 217; B 9302-107; B9302-107; B-9302-107; BYK 20869; BYK-20869; BYK20869; Daxas; Daliresp
IUPAC Name	3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide
Molecular Weight	403.207
Molecular Formula	C17H14Cl2F2N2O3
Canonical SMILES	C1CC1COC2=C(C=CC(=C2)C(=O)NC3=C(C=NC=C3Cl)Cl)OC(F)F
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
Boiling Point	430.6±45.0 °C at 760 mmHg
Melting Point	154-158°C
Flash Point	214.2±28.7 °C
Purity	99%
Density	1.5±0.1 g/cm3
Solubility	In vitro: 10 mM in DMSO
Appearance	White to off-White Solid
Storage	Powder: -20°C: 3 years 4°C: 2 years In solvent: -80°C: 6 months -20°C: 1 month
Animal Admin	Mice WT or pIgR-/- mice are used. For studies using Roflumilast, 200 μL of 0.5 mg/mL suspension of Roflumilast or vehicle (4% methylcellulose, 1.3% PEG400 and 5 μg drug per mg animal weight) is administered by oral gavage once daily, 5 days a week for the duration of treatment. Mice are treated daily by oral gavage with 100 μg of Roflumilast (5 μg/g) or vehicle (4% methylcellulose, 1.3% PEG400) for 3 months and lungs are harvested at 12 months of age.
Complexity	475
Exact Mass	402.0349540
Index Of Refraction	1.604
In Vitro	Roflumilast does not affect PDE enzymes apart from PDE4, and is a subnanomolar inhibitor of most PDE4 splicing variants tested. It showed no PDE4 subtype selectivity apart from PDE4C (4C1, IC50=3 nM; 4C2, IC50=4.3 nM), which is inhibited with a slightly lower potency. Roflumilast is a potent and selective PDE4 inhibitor. Roflumilast is a monoselective PDE4 inhibitor since it does not affect other PDE isoenzymes, including PDE1, PDE2, PDE3, and PDE5 up to 10,000-fold higher concentrations. Roflumilast inhibits human neutrophil functions. Roflumilast inhibits TNFα synthesis in monocyte-derived dendritic cells. Rolfumilast inhibits proliferation and cytokine synthesis in CD4+ T cells. Proliferation is inhibited to a maximum of about 60% by Roflumilast with a potency (IC30) of 7 nM.
In Vivo	Animal studies with Roflumilast demonstrated that it reduced the accumulation of neutrophils in bronchoalveolar lavage fluid following short-term exposure of guinea pigs, mice or rats to tobacco smoke, and following exposure of rats to a combination of tobacco smoke and bacterial lipopolysaccharide, and abolished the lung parenchymal influx of inflammatory cells seen in rats exposed to tobacco smoke for 7 months. Roflumilast blocks COPD progression in pIgR-/- mice. For these studies, 9-month-old WT or pIgR-/- mice are treated daily by oral gavage with 100 μg of Roflumilast (5 μg/g) or vehicle (4% methylcellulose, 1.3% PEG400) for 3 months and lungs are harvested at 12 months of age. Unlike pIgR-/- mice treated with vehicle, mice treated with Roflumilast had no progression of small airway wall remodelling after starting treatment. Strikingly, 12-month-old pIgR-/- mice treated with Roflumilast had reduced indices of emphysema compared with 9-month-old pIgR-/- mice, indicating that Roflumilast not only blocks progression of emphysema in this model but apparently facilitates some resolution of the emphysematous destruction of lung parenchyma.
PSA	6.45
Target	Phosphodiesterase (PDE); RSV
Vapor Pressure	1.28E-07mmHg at 25°C
XLogP3-AA	4.6