Vol. 290, Issue 1, 188-195, July 1999

Preclinical Evaluation of Anti-inflammatory Activities of the Novel Pyrrolopyrimidine PNU-142731A, a Potential Treatment for Asthma¹

Jia En Chin, Cheryl A. Hatfield, Greg E. Winterrowd, Raymond F. Krzesicki, Kathy L. Shull, Stephen F. Fidler, Karen P. Kolbasa, John R. Brashler, Robert L. Griffin, William E. Fleming, James M. Justen, Lee S. Banitt, Gordon L. Bundy and Ivan M. Richards

Pharmacology Department (J.E.C., C.A.H., G.E.W., R.F.K., K.L.S., S.F.F., K.P.K., J.R.B., R.L.G., W.E.F., J.M.J., I.M.R.) and Medicinal Chemistry (L.S.B., G.L.B.), Pharmacia and Upjohn, Inc., Kalamazoo, Michigan

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-) 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.