Biological Activity

• DescriptionPhosphodiesterases (PDEs) are a family of enzymes that catalyze the hydrolysis of cyclic adenosine monophosphate and cyclic guanosine monophosphate. Roflumilast is a potent inhibitor of both human PDE4B and PDE4D with IC50 values of 0.84 and 0.68nM, respectively, while it showed much less inhibitory activity against other forms of PDEs (IC50 values > 10μM)^[7]. In A549 cells, roflumilast at the dose of 1μM prevented EGF-stimulated increase in MUC5AC mRNA and protein production but did not change the basal MUC5AC expression, and also inhibited EGF-induced phosphorylation of tyrosine residues of different intracellular proteins (i.e. EGF receptor, phospho-p38- and p44/42-MAPK) and the upregulation of EGFR expression. In human isolated bronchus, the presence of 1μM roflumilast inhibited EGF-induced MUC5AC mRNA and protein expression^[8]. In A/J mice expressing wild type cystic fibrosis transmembrane conductance regulator (CFTR) and exposed to cigarette smoke or air, acute roflumilast (30nM) treatment increased CFTR-dependent chloride transport in both smoke- and air-exposed mice as compared to vehicle-treated group. Oral administration of roflumilast (5mg/kg/day, once per day) for five weeks activated CFTR and completely reversed cigarette smoke-induced adverse effects in vivo^[9].
• MechanismThe difluromethoxy group of roflumilast binds at the Q1 pocket of enzyme, while the cyclopropyl methoxy group binds at the Q2 pocket^[7].
• Cell Study
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  HEK293 cells	-	Function assay	15 min	Inhibition of PDE4 expressed in HEK293 cells coexpressing cyclic nucleotide gated ion channel mutant assessed as inhibition of NECA-induced cAMP production treated 15 mins before NECA challenge measured after 45 mins by FLIPR assay	20378348
  PBMC	-	Function assay	-	Inhibition of TNFalpha production in LPS-stimulated human PBMC preincubated before LPS challenge measured after 4 hrs by enzyme immunoassay, IC50=2e-05 μM	19256507
  sf21 cells	-	Function assay	-	Inhibition of human full length PDE4A4 expressed in baculovirus infected sf21 cells, IC50=0.35 nM	23806553

• Animal Study
  Dose	Guinea pig: 0.04 mg/kg - 4 mg/kg[3] (p.o.) Mice: 1 mg/kg, 5 mg/kg[4] (p.o.), 5 mg/kg - 10 mg/kg[5] (p.o.)
  Administration	p.o.
  Pharmacokinetics	Animal Mice[6] Rats[6] Dogs[6] Monkeys[6] Dose 12 mg/kg 20 mg/kg 2 mg/kg 0.5 mg/kg Administration p.o. p.o. p.o. p.o. F 0.25 0.11 0.19 0.48 T1/2 0.7 h 0.9 h 3.8 h 4.4 h AUC0→∞ 1663 μg·h/ml 643 μg·h/ml 1054 μg·h/ml 648 μg·h/ml Cmax 1313 μg/ml 94 μg/ml 106 μg/ml 341 μg/ml Vd 1.9 L/kg 5.1 L/kg 2.1 L/kg 2.1 L/kg CL 1.8 L/h/kg 3.9 L/h/kg 0.4 L/h/kg 0.3 L/h/kg

• Clinical Study

• NCT Number	Condition or disease	Phase	Recruitment Status	Estimated Study Completion Date	Locations
  NCT03762330	Chronic Obstructive Pulmonary ... more >>Disease Collapse <<	Not Applicable	Not yet recruiting	January 2021	-
  NCT02835716	-	-	Recruiting	September 2020	United States, Connecticut ... more >> Millennium Magnetic Technologies, LLC Recruiting Westport, Connecticut, United States, 06880 Contact: Steve Levy, MD    203-423-9494    SL@MilMag.net Contact: Donald H Marks, MD PhD    9733070364    DHM@MilMag.net Collapse <<
  NCT01730404	COPD	Phase 2	Completed	-	Ireland ... more >> Celerion Belfast, Ireland United Kingdom Parexel, early phases Harrow, United Kingdom Medicines Evaluation Unit Ltd Manchester, United Kingdom Freeman Hospital Newcastle, United Kingdom Nottingham University Hospitals NHS Trust Nottingham, United Kingdom Collapse <<

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