Preclinical evaluation of anti-inflammatory activities of the novel pyrrolopyrimidine PNU-142731A, a potential treatment for asthma

J E Chin, C A Hatfield, G E Winterrowd, R F Krzesicki, K L Shull, S F Fidler, K P Kolbasa, J R Brashler, R L Griffin, W E Fleming, J M Justen, L S Banitt, G L Bundy, I M Richards
Journal of Pharmacology and Experimental Therapeutics 1999, 290 (1): 188-95
The anti-inflammatory properties of a novel pyrrolopyrimidine, PNU-142731A, in a murine model of antigen-induced eosinophilic lung inflammation are described. PNU-142731A, when given orally, demonstrated a dose-related inhibition of eosinophil- and lymphocyte-rich accumulation in the airways of ovalbumin (OA)-sensitized and challenged (OA/OA) C57BL/6 mice. The magnitude of the suppression of lung inflammation was also dependent on length of treatment. Reductions in the levels of interleukin (IL)-5, IL-6, and IgA in the bronchoalveolar lavage fluid of treated OA/OA mice, when compared with vehicle-sensitized control mice (V/OA), were observed. Plasma concentrations of IL-5, total IgE, and OA-specific IgG1 were also lowered in OA/OA mice by treatment. Histological assessment of formalin-fixed lung tissue sections confirmed that the compound blocked the accumulation of eosinophils in the airway tissue. Furthermore, significantly less mucus glycoproteins were seen in the lungs of PNU-142731A-treated OA/OA mice. Reverse transcription-polymerase chain reaction of lung tissue from PNU-142731A-dosed OA/OA mice demonstrated that mRNA for Th2 cytokines was less than that in vehicle-treated OA/OA controls. OA-elicited production of IL-4 by disaggregated lung tissue cells from PNU-142371A-treated OA/OA mice was also less than that of controls. In contrast, the release of Th1 cytokines (IL-2 and interferon-gamma) were elevated. Similarly, the OA-stimulated release of Th2 cytokines (IL-5 and IL-10) by splenocytes from PNU-142731A-treated OA/OA mice were inhibited. Combined therapy of OA/OA mice with PNU-142731A and suboptimal doses of dexamethasone revealed that PNU-142731A had steroid-sparing effects. These characteristics of PNU-142731A in a murine model of allergic tissue inflammation support its clinical development as a potential treatment for asthma.

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