Review Pulmonary-Allergy, Dermatological, Gastrointestinal & Arthritis: Inhibitors of TNFα synthesis

Abstract

Tumour necrosis factor-α (TNFα) is a cytokine with a multitude of biological activities linked to the pathology of inflammation. Current anti-TNFα strategies include several protein-based approaches, one of which has produced positive results in the clinic. Most of the small molecules which specifically inhibit TNFα production do so by increasing intracellular cyclic adenosine monophosphate (cAMP) which ultimately blocks TNFα gene expression. The most important of these compounds are the rolipram and pentoxifylline-related phosphodiesterase IV (PDE IV) inhibitors which are being actively pursued by a number of pharmaceutical companies. The ability of thalidomide to block TNFα production contributes to its therapeutic properties in humans. Recent studies suggest that cell-associated TNFα may be necessary for normal host defence mechanisms. This finding has added to the excitement concerning the identification of a unique metalloproteinase enzyme which is responsible for the proteolytic processing of TNFα. Inhibitors of this matrix metalloproteinase-related enzyme have appeared in both the primary and patent literature. The therapeutic benefit of small molecule inhibitors of TNFα synthesis will likely be assessed in the near future.