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Discovery of BRL 50481 [3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene], a Selective Inhibitor of Phosphodiesterase 7: In Vitro Studies in Human Monocytes, Lung Macrophages, and CD8⁺ T-Lymphocytes

Thoracic Medicine, National Heart and Lung Institute, Imperial College London, London, United Kingdom (S.J.S., L.E.D., P.S.F., P.J.B.); Respiratory, Inflammation and Respiratory Pathogens Center for Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, Pennsylvania (L.B.C., M.S.B.); Department of Histopathology, Royal Brompton Hospital, London, United Kingdom (A.G.N.); and Departments of Cell Biology and Anatomy (R.N.) and Pharmacology and Therapeutics (M.A.G.), Respiratory Research Group, University of Calgary, Calgary, Alberta, Canada

The biochemical and pharmacological characteristics in human proinflammatory cells of BRL 50481 [3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene], a novel and selective inhibitor of phosphodiesterase (PDE) 7, are described. BRL 50481 inhibited the activity of hrPDE7A1 expressed in baculovirus-infected Spodoptera frugiperda 9 cells in a competitive manner (K_i value of 180 nM) and was 416 and 1884 times less potent against PDE3 and 38 and 238 times less potent against PDE4 at a substrate concentration of 1 µM and 50 nM cAMP, respectively. Western blotting identified HSPDE7A1 but not HSPDE7A2 in three human cell types that are implicated in the pathogenesis of chronic obstructive lung disease, namely, CD8⁺ T-lymphocytes, monocytes, and lung macrophages. BRL 50481 had no effect on the proliferation of CD8⁺ T-lymphocytes and only marginally (2-11%) reduced the generation of tumor necrosis factor (TNF) from blood monocytes and lung macrophages. However, in the presence of BRL 50481 the inhibitory effect of rolipram was enhanced on all three cell types. The expression of HSPDE7A1 was increased in a time-dependent manner in monocytes that were "aged" in culture medium. Under this condition, BRL 50481 now inhibited TNF generation in a concentration-dependent manner. In aged monocytes, rolipram, Org 9935 (a PDE3 inhibitor), and prostaglandin E₂ inhibited TNF generation in a concentration-dependent manner and interacted additively with BRL 50481. BRL 50481 is the first fully documented PDE7 inhibitor that has acceptable selectivity for in vitro studies. Furthermore, although BRL 50481 had only a modest inhibitory effect per se on the proinflammatory cells studied, it acted at least additively with other cAMP-elevating drugs, especially when HSPDE7A1 was up-regulated.

Address correspondence to: Dr. Mark A. Giembycz, Department of Pharmacology and Therapeutics, Respiratory Research Group, University of Calgary, 3330 Hospital Dr. NW, Calgary, AB, Canada T2N 4N1. E-mail: giembycz{at}ucalgary.ca

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