title: Preclinical evaluation of anti-inflammatory activities of the novel pyrrolopyrimidine PNU-142731A, a potential treatment for asthma.
abstract: 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.
authors.affiliation: Pharmacology Department, Pharmacia and Upjohn, Inc., Kalamazoo, Michigan, USA. Jia.E.Chin@am.pnu.com
authors.forename: J E
authors.initials: JE
authors.lastname: Chin
authors.forename: C A
authors.initials: CA
authors.lastname: Hatfield
authors.forename: G E
authors.initials: GE
authors.lastname: Winterrowd
authors.forename: R F
authors.initials: RF
authors.lastname: Krzesicki
authors.forename: K L
authors.initials: KL
authors.lastname: Shull
authors.forename: S F
authors.initials: SF
authors.lastname: Fidler
authors.forename: K P
authors.initials: KP
authors.lastname: Kolbasa
authors.forename: J R
authors.initials: JR
authors.lastname: Brashler
authors.forename: R L
authors.initials: RL
authors.lastname: Griffin
authors.forename: W E
authors.initials: WE
authors.lastname: Fleming
authors.forename: J M
authors.initials: JM
authors.lastname: Justen
authors.forename: L S
authors.initials: LS
authors.lastname: Banitt
authors.forename: G L
authors.initials: GL
authors.lastname: Bundy
authors.forename: I M
authors.initials: IM
authors.lastname: Richards
mesh_terms: D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D007070:Immunoglobulin A / Q000378:metabolism; D007073:Immunoglobulin E / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D007136:Immunoglobulins / Q000096:biosynthesis; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009093:Mucus / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology; D011759:Pyrrolidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012137:Respiratory System / Q000187:drug effects / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D018927:Anti-Asthmatic Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007136:Immunoglobulins; D007211:Indoles; C120149:PNU 142731A; D011759:Pyrrolidines; D012333:RNA, Messenger; D015842:Serine Proteinase Inhibitors; D007073:Immunoglobulin E; D010047:Ovalbumin