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.

Abstract

AWD 12-281 is a potent (IC(50) = 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 alpha (TNF alpha). The corresponding values for half-maximum inhibition, EC(50), 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 TNF alpha release in dispersed nasal polyps (EC(50) = 111 nM) and in diluted whole blood (EC(50) = 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.

• Authors: Regina Draheim, Ute Egerland, Chris Rundfeldt
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 308 Issue 2 Pg. 555-63 (Feb 2004) ISSN: 0022-3565 [Print] United States
• PMID: 14610230 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AWD 12-281
• Amides
• Aminopyridines
• Anti-Inflammatory Agents
• Benzamides
• Cyclohexanecarboxylic Acids
• Cyclopropanes
• Cytokines
• Indoles
• Interleukin-2
• Interleukin-5
• Nitriles
• Phosphodiesterase Inhibitors
• Tumor Necrosis Factor-alpha
• Roflumilast
• Interleukin-4
• Cilomilast
• 3',5'-Cyclic-AMP Phosphodiesterases
• Cyclic Nucleotide Phosphodiesterases, Type 4

Topics

• 3',5'-Cyclic-AMP Phosphodiesterases (antagonists & inhibitors)
• Amides (pharmacology)
• Aminopyridines (pharmacology)
• Anti-Inflammatory Agents (pharmacology)
• Benzamides (pharmacology)
• Cyclic Nucleotide Phosphodiesterases, Type 4
• Cyclohexanecarboxylic Acids (pharmacology)
• Cyclopropanes
• Cytokines (metabolism)
• Humans
• Indoles (pharmacology)
• Interleukin-2 (metabolism)
• Interleukin-4 (metabolism)
• Interleukin-5 (metabolism)
• Leukocytes, Mononuclear (drug effects, metabolism)
• Nitriles
• Phosphodiesterase Inhibitors (pharmacology)
• Polyps (pathology)
• Tumor Necrosis Factor-alpha (metabolism)