Preclinical evaluation of anti-inflammatory activities of the novel pyrrolopyrimidine PNU-142731A, a potential treatment for asthma.
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.
Chin
J E
JE
Pharmacology Department, Pharmacia and Upjohn, Inc., Kalamazoo, Michigan, USA. Jia.E.Chin@am.pnu.com
Hatfield
C A
CA
Winterrowd
G E
GE
Krzesicki
R F
RF
Shull
K L
KL
Fidler
S F
SF
Kolbasa
K P
KP
Brashler
J R
JR
Griffin
R L
RL
Fleming
W E
WE
Justen
J M
JM
Banitt
L S
LS
Bundy
G L
GL
Richards
I M
IM
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
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