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 (PBMCs), 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 PBMCs: interleukin-2 (IL-2, phytohemagglutinin stimulation), IL-5 (concanavalin A stimulation), IL-5 and IL-4 (anti-CD3/anti-CD28 costimulation), and lipopolysaccharide-stimulated release of tumor necrosis factor α (TNFα). 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 1-(3-nitrophenyl)-3-(4-pyridylmethyl)pyrido[2,3-d]pyrimidin-2,4(1H,3H)-dione (RS-25344-000), it could be shown that the PDE4 inhibitory activity was closely correlated with inhibitory potential as measured by the above-described assays. AWD 12-281 was also shown to suppress TNFα 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.
Footnotes
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Parts of the project were supported by the European Union fund for regional development and by the Free State of Saxony (project SAB 8093).
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DOI: 10.1124/jpet.103.059097.
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ABBREVIATIONS: PDE, phosphodiesterase; COPD, chronic obstructive pulmonary disease; PBMC, peripheral blood mononuclear cell; TNFα, tumor necrosis factor α; IL, interleukin; FCS, fetal calf serum; PBS, phosphate-buffered saline; LPS, lipopolysaccharide; DMSO, dimethyl sulfoxide; PMNL, polymorphonuclear leukocyte; ELISA, enzyme-linked immunosorbent assay; PHA-P, phytohemagglutinin P; cilomilast, SB 207499; RPR-73401, piclamilast; RS-25344-000, 1-(3-nitrophenyl)-3-(4-pyridylmethyl)pyrido[2,3-d]pyrimidin-2,4(1H,3H)-dione.
- Received August 25, 2003.
- Accepted October 28, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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Anti-Inflammatory Potential of the Selective Phosphodiesterase 4 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
