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162401-32-3

162401-32-3 structure
162401-32-3 structure
  • Name: Roflumilast
  • Chemical Name: roflumilast
  • CAS Number: 162401-32-3
  • Molecular Formula: C17H14Cl2F2N2O3
  • Molecular Weight: 403.207
  • Catalog: API Respiratory medication Asthma
  • Create Date: 2018-08-13 11:33:24
  • Modify Date: 2024-01-02 17:05:55
  • Roflumilast is a selective PDE4 inhibitor with IC50s of 0.7, 0.9, 0.7, and 0.2 nM for PDE4A1, PDEA4, PDEB1, and PDEB2, respectively, without affecting PDE1, PDE2, PDE3 or PDE5 isoenzymes from various cells.
Name roflumilast
Synonyms Daxas
EINECS 223-583-8
3-(Cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)benzamide
Benzamide, 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)-
MFCD00938270
Roflumilast
3-(CYCLOPROPYLMETHOXY)-N-(3,5-DICHLOROPYRIDIN-4-YL)-4-(DIFLUOROMETHOXY)BENZAMIDE
Daliresp
Description Roflumilast is a selective PDE4 inhibitor with IC50s of 0.7, 0.9, 0.7, and 0.2 nM for PDE4A1, PDEA4, PDEB1, and PDEB2, respectively, without affecting PDE1, PDE2, PDE3 or PDE5 isoenzymes from various cells.
Related Catalog
Target

IC50: 0.7 nM (PDE4A1), 0.9 nM (PDE4A4), 0.7 nM (PDE4B1), 0.2 nM (PDE4B2)[1]

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[2]. 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[3].
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[2]. 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[4].
Kinase Assay PDE activity is determined with some modifications. The assay mixture contain 50 mM Tris (pH 7.4), 5 mM MgCl2, 0.5 μM cAMP or cGMP, and [3H]cAMP or [3H]cGMP (about 30,000 cpm/assay), the indicated concentration of the inhibitor and an aliquot of the enzyme solution at a final assay volume of 200 μL. Stock solutions of the compounds are diluted 1:100 (v/v) in the Tris buffer mentioned above; appropriate dilutions are prepared in 1% (v/v) DMSO/Tris buffer, which are diluted 1:2 (v/v) in the assays to obtain the desired final concentrations of the inhibitors at a DMSO concentration of 0.5% (v/v). DMSO itself affected none of the PDE activities. After preincubation for 5 min at 37°C, the reaction is started by the addition of substrate (cAMP or cGMP) and the assays are incubated for further 15 min at 37°C. Then 50 μL of 0.2 N HCl is added to stop the reaction and the assays are left on ice for about 10 min. Following incubation with 25 μg of 5′-nucleotidase (Crotalus atrox snake venom) for 10 min at 37°C, the assays are loaded on QAE Sephadex A-25 (1 mL of bed volume in Poly-Prep chromatography columns). The columns are eluted with 2 mL of 30 mM ammonium formate (pH 6.0) and the eluate is counted for radioactivity. Results are corrected for blank values (measured in the presence of denatured protein) that are below 5% of total radioactivity. The amount of cyclic nucleotides hydrolyzed did not exceed 30% of the original substrate concentration[3].
Animal Admin Mice[4] 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.
References

[1]. Hatzelmann A, et al. The preclinical pharmacology of roflumilast--a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2010 Aug;23(4):235-56.

[2]. Rabe KF. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br J Pharmacol. 2011 May;163(1):53-67.

[3]. Hatzelmann A, et al. Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J Pharmacol Exp Ther. 2001 Apr;297(1):267-79.

[4]. Richmond BW, et al. Airway bacteria drive a progressive COPD-like phenotype in mice with polymeric immunoglobulin receptor deficiency. Nat Commun. 2016 Apr 5;7:11240.

[5]. Ding H, et al. Treatment of obesity-associated overactive bladder by the phosphodiesterase type-4 inhibitor roflumilast. Int Urol Nephrol. 2017 Jul 29.
Density 1.5±0.1 g/cm3
Boiling Point 430.6±45.0 °C at 760 mmHg
Melting Point 158°C
Molecular Formula C17H14Cl2F2N2O3
Molecular Weight 403.207
Flash Point 214.2±28.7 °C
Exact Mass 402.034943
PSA 60.45000
LogP 4.84
Vapour Pressure 0.0±1.0 mmHg at 25°C
Index of Refraction 1.604
Storage condition Refrigerator
Symbol GHS07
GHS07
Signal Word Warning
Hazard Statements H315-H319-H335
Precautionary Statements P261-P305 + P351 + P338
Hazard Codes Xi
Risk Phrases 36/37/38
Safety Phrases 26
RIDADR NONH for all modes of transport

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title: CAS No. 162401-32-3 | Chemsrc address: https://www.chemsrc.com/en/baike/81631.html

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