Roflumilast

Roflumilast is a selective inhibitor of PDE4 with IC50 of 0.2-4.3 nM.

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Roflumilast  Chemical Structure

Roflumilast Chemical Structure
Molecular Weight: 403.21

Validation & Quality Control

Customer Reviews(1)

Quality Control & MSDS

Related Compound Libraries

Roflumilast is available in the following compound libraries:

Product Information

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Product Description

Biological Activity

Description Roflumilast is a selective inhibitor of PDE4 with IC50 of 0.2-4.3 nM.
Targets PDE4B2 [1] PDE4A1 [1] PDE4B1 [1] PDE4A4 [1] PDE4C1 [1] PDE4C2 [1]
IC50 0.2 nM 0.7 nM 0.7 nM 0.9 nM 3 nM 4.3 nM
In vitro Roflumilast displays anti-inflammatory and immunomodulatory in vitro. Roflumilast inhibits LTB4 synthesis in human neutrophil with IC50 of 2 nM. Roflumilast inhibits fMLP-stimulated ROS formation as luminol-enhanced CL in human neutrophils or eosinophils with IC35 of 4 nM, and 7 nM, repectively. Roflumilast inhibits LPS-stimulated TNF-α synthesis in monocytes with IC40 of 21 nM. Roflumilast inhibits TNF-α synthesis in monocyte-derived dendritic cells with IC20 of 5 nM. Rolfumilast inhibits anti-CD3 and anti-CD28 antibody-stimulated proliferation of CD4+ T cells with IC30 of 7 nM. Rolfumilast inhibits anti-CD3 and anti-CD28 antibody-stimulated synthesis of IL-2, IL-4, IL-5, and IFN-v in CD4+ T cells with IC20 of 1 nM, IC30 of 7 nM, IC25 of 13 nM, and IC35 of 8 nM, respectively. [2]
In vivo Roflumilast is activity against pulmonary inflammatory response related to COPD in animal model. Roflumilast (5 mg/kg/day) induces reduction of neutrophils, macrophages, DC, B-cells, CD4+ T cells, CD8+ T cells in the lung of mice exposed to tobacco smoke for 7 month by 78%, 82%, 48%, 100%, 98%, and 88%, respectively. [3] Roflumilast is an efficient inhibitor of lung fibrotic remodeling. Roflumilast dose-dependently diminishes total lung hydroxyproline after bleomycin, attaining about 47% inhibition at 5 mg/kg/day, paralleled by a reduction in lung αI(I) collagen transcripts and fibrotic lesions. Roflumilast reduces oxidative stress in vivo. Roflumilast (5 mg/kg/day) moderately reduces an increase in BAL fluid lipid hydroperoxides measured at day 14 after intratracheal bleomycin administration in mice. [4]
Features

Protocol(Only for Reference)

Kinase Assay: [2]

PDE activity assay The assay mixture contains 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; 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 affects none of the PDE activity. After preincubation for 5 min at 37 ℃, the reaction is started by the addition of substrate (cAMP or cGMP) and the assays are incubated for further 15 min at 37 ℃. 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 for 10 min at 37 ℃, the assays are loaded on QAE Sephadex A-25 (1 mL of bed volume in Poly-Prep chromatography column). 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 does not exceed 30% of the original substrate concentration.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Hatzelmann A, et al. Pulm Pharmacol Ther, 2010, 23(4), 235-256.

[2] Hatzelmann A, et al. J Pharmacol Exp Ther, 2001, 297(1), 267-279.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2014-10-16)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02165826 Recruiting Chronic Obstructive Pulmonary Disease (COPD) Takeda May 2014 Phase 3
NCT02187250 Completed PCOS|Obesity University Medical Centre Ljubljana March 2014 Phase 4
NCT02079844 Recruiting Schizophrenia Takeda March 2014 Phase 1
NCT02051335 Completed Memory Impairment|Alzheimers Disease Takeda January 2014 Phase 1
NCT02018432 Not yet recruiting Chronic Obstructive Pulmonary Disease Asan Medical Center December 2013 Phase 4

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Chemical Information

Download Roflumilast SDF
Molecular Weight (MW) 403.21
Formula

C17H14Cl2F2N2O3

CAS No. 162401-32-3
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms
Solubility (25°C) * In vitro DMSO 81 mg/mL (200 mM)
Water <1 mg/mL (<1 mM)
Ethanol 18 mg/mL (44 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Research Area

Customer Reviews (1)


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Rating
Source J Mass Spectrom 2012 47, 1612-1619 . Roflumilast purchased from Selleck
Method pharmacokinetic study
Cell Lines wistar rats
Concentrations 0.5 mg/kg
Incubation Time 1-24 h
Results The plasma concentration time profiles of IC87114 , RFM and its active metabolite RFN are shown in this Figue and could be traceable up to 24 h, 12 h and 8 h, respectively.

Product Citations (1)

Tech Support & FAQs

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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