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Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro.
J Pharmacol Exp Ther 2001; 297(1):267-79JP

Abstract

From a series of benzamide derivatives, roflumilast (3-cyclo-propylmethoxy-4-difluoromethoxy-N-[3,5-di-chloropyrid-4-yl]-benzamide) was identified as a potent and selective PDE4 inhibitor. It inhibits PDE4 activity from human neutrophils with an IC(50) of 0.8 nM without affecting PDE1 (bovine brain), PDE2 (rat heart), and PDE3 and PDE5 (human platelets) even at 10,000-fold higher concentrations. Roflumilast is almost equipotent to its major metabolite formed in vivo (roflumilast N-oxide) and piclamilast (RP 73401), however, more than 100-fold more potent than rolipram and Ariflo (cilomilast; SB 207499). The anti-inflammatory and immunomodulatory potential of roflumilast and the reference compounds was investigated in various human leukocytes using cell-specific responses: neutrophils [N-formyl-methyl-leucyl-phenylalanine (fMLP)-induced formation of LTB(4) and reactive oxygen species (ROS)], eosinophils (fMLP- and C5a-induced ROS formation), monocytes, monocyte-derived macrophages, and dendritic cells (lipopolysaccharide-induced tumor necrosis factor-alpha synthesis), and CD4+ T cells (anti-CD3/anti-CD28 monoclonal antibody-stimulated proliferation, IL-2, IL-4, IL-5, and interferon-gamma release). Independent of the cell type and the response investigated, the corresponding IC values (for half-maximum inhibition) of roflumilast were within a narrow range (2-21 nM), very similar to roflumilast N-oxide (3-40 nM) and piclamilast (2-13 nM). In contrast, cilomilast (40-3000 nM) and rolipram (10-600 nM) showed greater differences with the highest potency for neutrophils. Compared with neutrophils and eosinophils, representing the terminal inflammatory effector cells, the relative potency of roflumilast and its N-oxide for monocytes, CD4+ T cells, and dendritic cells is substantially higher compared with cilomilast and rolipram, probably reflecting an improved immunomodulatory potential. The efficacy of roflumilast in vitro and in vivo (see accompanying article in this issue) suggests that roflumilast will be useful in the treatment of chronic inflammatory disorders such as asthma and chronic obstructive pulmonary disease.

Authors+Show Affiliations

Byk Gulden, Department of Biochemistry, P.O. Box 100301, 48403 Konstanz, Germany. armin.hatzelmann@byk.deNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

11259554

Citation

Hatzelmann, A, and C Schudt. "Anti-inflammatory and Immunomodulatory Potential of the Novel PDE4 Inhibitor Roflumilast in Vitro." The Journal of Pharmacology and Experimental Therapeutics, vol. 297, no. 1, 2001, pp. 267-79.
Hatzelmann A, Schudt C. Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J Pharmacol Exp Ther. 2001;297(1):267-79.
Hatzelmann, A., & Schudt, C. (2001). Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. The Journal of Pharmacology and Experimental Therapeutics, 297(1), pp. 267-79.
Hatzelmann A, Schudt C. Anti-inflammatory and Immunomodulatory Potential of the Novel PDE4 Inhibitor Roflumilast in Vitro. J Pharmacol Exp Ther. 2001;297(1):267-79. PubMed PMID: 11259554.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. AU - Hatzelmann,A, AU - Schudt,C, PY - 2001/3/22/pubmed PY - 2001/5/5/medline PY - 2001/3/22/entrez SP - 267 EP - 79 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 297 IS - 1 N2 - From a series of benzamide derivatives, roflumilast (3-cyclo-propylmethoxy-4-difluoromethoxy-N-[3,5-di-chloropyrid-4-yl]-benzamide) was identified as a potent and selective PDE4 inhibitor. It inhibits PDE4 activity from human neutrophils with an IC(50) of 0.8 nM without affecting PDE1 (bovine brain), PDE2 (rat heart), and PDE3 and PDE5 (human platelets) even at 10,000-fold higher concentrations. Roflumilast is almost equipotent to its major metabolite formed in vivo (roflumilast N-oxide) and piclamilast (RP 73401), however, more than 100-fold more potent than rolipram and Ariflo (cilomilast; SB 207499). The anti-inflammatory and immunomodulatory potential of roflumilast and the reference compounds was investigated in various human leukocytes using cell-specific responses: neutrophils [N-formyl-methyl-leucyl-phenylalanine (fMLP)-induced formation of LTB(4) and reactive oxygen species (ROS)], eosinophils (fMLP- and C5a-induced ROS formation), monocytes, monocyte-derived macrophages, and dendritic cells (lipopolysaccharide-induced tumor necrosis factor-alpha synthesis), and CD4+ T cells (anti-CD3/anti-CD28 monoclonal antibody-stimulated proliferation, IL-2, IL-4, IL-5, and interferon-gamma release). Independent of the cell type and the response investigated, the corresponding IC values (for half-maximum inhibition) of roflumilast were within a narrow range (2-21 nM), very similar to roflumilast N-oxide (3-40 nM) and piclamilast (2-13 nM). In contrast, cilomilast (40-3000 nM) and rolipram (10-600 nM) showed greater differences with the highest potency for neutrophils. Compared with neutrophils and eosinophils, representing the terminal inflammatory effector cells, the relative potency of roflumilast and its N-oxide for monocytes, CD4+ T cells, and dendritic cells is substantially higher compared with cilomilast and rolipram, probably reflecting an improved immunomodulatory potential. The efficacy of roflumilast in vitro and in vivo (see accompanying article in this issue) suggests that roflumilast will be useful in the treatment of chronic inflammatory disorders such as asthma and chronic obstructive pulmonary disease. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/11259554/Anti_inflammatory_and_immunomodulatory_potential_of_the_novel_PDE4_inhibitor_roflumilast_in_vitro_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11259554 DB - PRIME DP - Unbound Medicine ER -