Pharmacia is developing PNU-142731A, a potential lead compound as a treatment for asthma [294718]. It is in phase I clinical trials. PNU-142731A is a potent inhibitor of eosinophilic lung inflammation in rodents, and shows a good bioavailability profile in animals; the mechanism of action is being investigated. Unlike the original compound PNU-104067F, PNU-142731A does not give rise to gall bladder toxicity [295987], [298023].

01 Jan 2000·Journal of Biochemical and Molecular ToxicologyQ4 · MEDICINE

Effects of new antioxidant compounds PNU-104067F and PNU-74389G on antioxidant defense in normal and diabetic rats

Q4 · MEDICINE

Article

Author: Ruth A. Sanders ; John B. Watkins ; Frederick M. Rauscher

Diabetes mellitus and its complications are associated with elevated oxidative stress, leading to much interest in antioxidant compounds as possible therapeutic agents. Two new classes of antioxidant compounds, the pyrrolopyrimidines and the 21-aminosteroids, are known to inhibit lipid peroxidation and other biomolecular oxidation. We hypothesized that in the presence of excess oxidants or the impaired antioxidant defense seen in diabetes mellitus, administration of antioxidants such as these may reverse the effects of diabetes on antioxidant parameters. This study measured the effects of subchronic (14 day) treatment with a pyrrolopyrimidine (PNU-104067F) or a 21-aminosteroid (PNU-74389G) in normal and diabetic Sprague-Dawley rats. Activity levels of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase, concentrations of oxidized and reduced glutathione, and lipid peroxidation were used as measures of antioxidant defense in liver, kidney, heart, and brain tissue. In normal rats, the only effect was a 43% increase in cardiac lipid peroxidation after treatment with PNU-104067F. In diabetic rats, the only reversals of the effects of diabetes were a 30% decrease in hepatic glutathione peroxidase activity after PNU-74389G treatment and a 33% increase in cardiac glutathione disulfide concentration after PNU-104067F treatment. In contrast to these effects, increased cardiac glutathione peroxidase and catalase activities, increased brain glutathione peroxidase activity, increased hepatic lipid peroxidation, decreased hepatic glutathione content, and decreased hepatic catalase activity were seen in diabetic rats, reflecting an exacerbation of the effects of diabetes.

01 May 1998·Journal of Cerebral Blood Flow & MetabolismQ2 · MEDICINE

Neuroprotective Efficacy and Mechanisms of Novel Pyrrolopyrimidine Lipid Peroxidation Inhibitors in the Gerbil Forebrain Ischemia Model

Q2 · MEDICINE

Article

Author: Hall, Edward D. ; Dunn, Edwige ; Oostveen, Jo A. ; Carter, Donald B.

A brief period of bilateral carotid occlusion (BCO)-induced forebrain ischemia in gerbils triggers neuronal degeneration and the subsequent expression of amyloid precursor protein (APP), b-amyloid protein (b-AP), and apolipoprotein E (APO-E) in the selectively vulnerable CA, region of the hippocampus. The increase in immunoreactivity is secondary to the postischemic degeneration of the CA1 neurons and is largely astrocyte-derived as evidenced by a simultaneous increase in glial fibrillary acidic protein (GFAP) staining. Oxygen radical-induced lipid peroxidation has been strongly suggested to play a role in postischemic neuronal damage and Alzheimer's disease. Recent literature suggests a possible link between early oxidative stress and APP overexpression. Therefore, the present investigation examined the effect of two novel brain-penetrating pyrrolopyrimidine lipid peroxidation inhibitors (PNU-101033E and PNU-104067F) on CA1 neurodegeneration and the subsequent increase in APP, b-AP, APO-E, and GFAP immunostaining at 4 days after a 5-minute episode of forebrain ischemia. Using an antibody for lipid peroxidation–derived malondialdehyde (MDA)-modified proteins, the authors also examined the effects of PNU-104067F on MDA immunostaining 2 days after ischemia, before completion of the neuronal loss. At 2 days, the authors also evaluated microglial activation using an antibody to surface major histocompatibility complex class II antigen expressed by activated microglia. Gerbils were treated at 30 mg/kg orally 30 minutes before the BCO and 2 hours after ischemia, followed by daily dosing for the next day (microglia and MDA) and the successive 3 days for APP, b-AP, APO-E, and GFAP immunostaining. APP and APO-E staining was significantly suppressed by 50% and 66%, respectively, with either compound. b-AP immunoreactivity was decreased 56% with both compounds, and GFAP expression was significantly decreased 53% (PNU-101033E) and 60.5% (PNU-104067F). There was a concomitant partial sparing of the CA1 hippocampal neurons by both PNU-101033E and PNU-104067F ( P<.01) as determined by cresyl violet histochemistry. PNU-104067F significantly inhibited lipid peroxidation-derived MDA immunostaining and microglia activation ( P<.05) at 48 hours after ischemia. Brain-penetrable lipid peroxidation inhibitors may provide attenuation of various glial response proteins after ischemic injury, probably secondary to neuronal protection.

100 Deals associated with PNU-104067F

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 1	-	Atos SE	-
Asthma	Phase 1	-	Freie Universität Berlin	-
Asthma	Phase 1	US	Pharmacia Corp.	-
Neurodegenerative Diseases	Phase 1	US	Pharmacia Corp.	-

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