Reference

Inhibition of inflammation and remodeling by roflumilast and dexamethasone in murine chronic asthma

Inhibition of inflammation and remodeling by roflumilast and dexamethasone in murine chronic asthma. Kumar, Rakesh K.; Herbert, Cristan; Thomas, Paul S.; Wollin, Lutz; Beume, Rolf; Yang, Ming; Webb, Dianne C.; Foster, Paul S. ( Department of Pathology, University of New South Wales, Sydney, Australia). Journal of Pharmacology and Experimental Therapeutics, 307(1), 349-355 (English) 2003 American Society for Pharmacology and Experimental Therapeutics.Some commonly used reagents like 50-02-2 and 162401-32-3 are used in this experiment. CODEN: JPETAB. ISSN: 0022-3565. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Section cross-reference(s): 2 Phosphodiesterase (PDE) inhibitors have potential as alternatives or adjuncts to glucocorticoid therapy in asthma. We compared roflumilast (a selective PDE4 inhibitor) with pentoxifylline (a nonselective inhibitor) and dexamethasone in ameliorating the lesions of chronic asthma in a mouse model. BALB/c mice sensitized to ovalbumin were chronically challenged with aerosolized antigen for 6 wk. During weeks 5 and 6, groups of animals were treated with roflumilast or dexamethasone by daily gavage or with pentoxifylline by daily i.p. injection. Airway hyper-reactivity (AHR) was evaluated by wholebody plethysmog. and airway lesions by histomorphometry and immunohistochem. Compared with vehicle alone, treatment with roflumilast or dexamethasone significantly reduced accumulation of eosinophils and chronic inflammatory cells, subepithelial collagenization, and thickening of the airway epithelium. Dexamethasone also reduced goblet cell hyperplasia/metaplasia, subepithelial accumulation of transforming growth factor-b1, and epithelial cytoplasmic immunoreactivity for nuclear factor-kB. Treatment with pentoxifylline inhibited only eosinophil recruitment and epithelial thickening. Roflumilast and dexamethasone slightly decreased AHR, whereas this was significantly reduced by pentoxifylline. Thus, in this model of chronic asthma, both roflumilast and dexamethasone were potent inhibitors of airway inflammation and remodeling. Roflumilast did not diminish accumulation of transforming growth factor-b1, suggesting that it might affect remodeling by mechanisms distinct from glucocorticoids. .

Structural Basis for the Activity of Drugs that Inhibit Phosphodiesterases

Structural Basis for the Activity of Drugs that Inhibit Phosphodiesterases. Card, Graeme L.; England, Bruce P.; Suzuki, Yoshihisa; Fong, Daniel; Powell, Ben; Lee, Byunghun; Luu, Catherine; Tabrizizad, Maryam; Gillette, Sam; Ibrahim, Prabha N.; Artis, Dean R.; Bollag, Gideon; Milburn, Michael V.; Kim, Sung-Hou; Schlessinger, Joseph; Zhang, Kam Y. J. (Plexxikon, Inc., Berkeley, CA 94710, USA). Structure (Cambridge, MA, United States), 12(12), 2233-2247 (English) 2004 Cell Press. CODEN: STRUE6. ISSN: 0969-2126. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Section cross-reference(s): 7, 75 Phosphodiesterases (PDEs) comprise a large family of enzymes that catalyze the hydrolysis of cAMP or cGMP and are implicated in various diseases. The authors describe the high-resoln. crystal structures of the catalytic domains of PDE4B, PDE4D, and PDE5A with ten different inhibitors, including the drug candidates cilomilast and roflumilast, for respiratory diseases. These cocrystal structures reveal a common scheme of inhibitor binding to the PDEs: (i) a hydrophobic clamp formed by highly conserved hydrophobic residues that sandwich the inhibitor in the active site; (ii) hydrogen bonding to an invariant glutamine that controls the orientation of inhibitor binding. A scaffold can be readily identified for any given inhibitor based on the formation of these two types of conserved interactions. 61413-54-5 and 162401-32-3 are just another two chemicals used in this study. These structural insights will enable the design of isoform-selective inhibitors with improved binding affinity and should facilitate the discovery of more potent and selective PDE inhibitors for the treatment of a variety of diseases. .