TY - JOUR T1 - Preclinical Evaluation of Anti-inflammatory Activities of the Novel Pyrrolopyrimidine PNU-142731A, a Potential Treatment for Asthma JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 188 LP - 195 VL - 290 IS - 1 AU - Jia En Chin AU - Cheryl A. Hatfield AU - Greg E. Winterrowd AU - Raymond F. Krzesicki AU - Kathy L. Shull AU - Stephen F. Fidler AU - Karen P. Kolbasa AU - John R. Brashler AU - Robert L. Griffin AU - William E. Fleming AU - James M. Justen AU - Lee S. Banitt AU - Gordon L. Bundy AU - Ivan M. Richards Y1 - 1999/07/01 UR - http://jpet.aspetjournals.org/content/290/1/188.abstract N2 - 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-γ) 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. The American Society for Pharmacology and Experimental Therapeutics ER -