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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 10, 2003; DOI: 10.1124/jpet.103.059097

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Regina Draheim
Ute Egerland
Chris Rundfeldt
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Received for publication August 26, 2003.
Revised October 20, 2003.
Accepted for publication October 28, 2003.

Anti-inflammatory Potential of the Selective PDE4 Inhibitor N-(3,5-Dichloro-pyrid-4-yl)-[1-(4-fluorobenzyl)- 5-hydroxy-indole-3-yl]-glyoxylic Acid Amide (AWD 12-281), in Human Cell Preparations

Regina Draheim 1*, Ute Egerland 2, Chris Rundfeldt 3

1 elbion AG, Department of Pharmacology, Meissner Str. 191, D-01445 Radebeul, Germany 2 elbion AG, Department of Molecular Biology, Meissner Str. 191, D-01445 Radebeul, Germany 3 elbion AG, Meissner Str. 191, D-01445 Radebeul, Germany

* Address correspondence to: E-mail: regina.draheim{at}elbion.de

Abstract

AWD 12-281 is a potent (IC50 9.7 nM) and highly selective inhibitor of the phosphodiesterase 4 (PDE4) isoenzyme with low affinity to the high-affinity rolipram-binding site. The compound was optimized for topical treatment of asthma, chronic obstructive pulmonary disease (COPD) and allergic rhinitis. The aim of the present study was to assess the effect of AWD 12- 281 in human inflammatory cells. Peripheral blood mononuclear cells (PBMC), diluted whole blood and human nasal polyp cells derived from surgically resected nasal polyps from patients with polyposis comprise sources of target tissue cells that can be used to predict anti- inflammatory effects in patients. AWD 12-281 was capable of suppressing the production of cytokines in stimulated PBMC: Interleukin-2 (IL-2, phytohemagglutinin (PHA)- stimulation), IL-5 (concanavalin A (Con A) stimulation), IL-5 and IL-4 (anti-CD3/anti-CD28 co-stimulation) and LPS- stimulated release of tumor necrosis factor{alpha} (TNF {alpha}). The corresponding values for half-maximum inhibition, EC50, for AWD 12-281 were within a narrow range (46-121 nM). Comparing the effect of AWD 12- 281 with roflumilast, cilomilast (SB 207499), rolipram, RPR-73401 and RS-253444-000, it could be shown that the PDE4 inhibitory activity was closely correlated with inhibitory potential as measured by the above assays. AWD 12-281 was also shown to suppress TNF{alpha} release in dispersed nasal polyps (EC50 111 nM) and in diluted whole blood (EC50 934 nM). The reduced activity in human blood may be related to high plasma protein binding. Currently, Phase-II clinical studies are under way to evaluate the therapeutic potential of AWD 12- 281 in asthma, COPD and allergic rhinitis.


Key words: Interleukin 2, Interleukin 4, Tumor necrosis factor alpha, interleukin 5, nasal polyps, peripheral blood mononuclear cells (PBMC)


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