Identification and Characterization of Novel Microsomal Prostaglandin E Synthase-1 Inhibitors for Analgesia

Prostaglandin (PG) E2 plays a critical role in eliciting inflammation. Nonsteroidal anti-inflammatory drugs and selective inhibitors of cyclooxygenase, which block PGE2 production, have been used as key agents in treating inflammation and pain associated with arthritis and other conditions. However,...

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Bibliographic Details
Published in:The Journal of pharmacology and experimental therapeutics 2016-03, Vol.356 (3), p.635-644
Main Authors: Chandrasekhar, Srinivasan, Harvey, Anita K, Yu, Xiao-Peng, Chambers, Mark G, Oskins, Jennifer L, Lin, Chaohua, Seng, Thomas W, Thibodeaux, Stefan J, Norman, Bryan H, Hughes, Norman E, Schiffler, Matthew A, Fisher, Matthew J
Format: Article
Language:English
Subjects:
Analgesia - methods
Analgesics - chemistry
Analgesics - pharmacology
Animals
Celecoxib - chemistry
Celecoxib - pharmacology
Cell Line, Tumor
Dose-Response Relationship, Drug
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Guinea Pigs
Humans
Imidazoles - chemistry
Imidazoles - pharmacology
Intramolecular Oxidoreductases - antagonists & inhibitors
Intramolecular Oxidoreductases - metabolism
Male
Microsomes - drug effects
Microsomes - enzymology
Pain Measurement - drug effects
Pain Measurement - methods
Phenanthrenes - chemistry
Phenanthrenes - pharmacology
Prostaglandin-E Synthases
Rats
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Summary:Prostaglandin (PG) E2 plays a critical role in eliciting inflammation. Nonsteroidal anti-inflammatory drugs and selective inhibitors of cyclooxygenase, which block PGE2 production, have been used as key agents in treating inflammation and pain associated with arthritis and other conditions. However, these agents have significant side effects such as gastrointestinal bleeding and myocardial infarction, since they also block the production of prostanoids that are critical for other normal physiologic functions. Microsomal prostaglandin E2 synthase-1 is a membrane-bound terminal enzyme in the prostanoid pathway, which acts downstream of cyclooxygenase 2 and is responsible for PGE2 production during inflammation. Thus, inhibition of this enzyme would be expected to block PGE2 production without inhibiting other prostanoids and would provide analgesic efficacy without the side effects. In this report, we describe novel microsomal prostaglandin E2 synthase-1 inhibitors that are potent in blocking PGE2 production and are efficacious in a guinea pig monoiodoacetate model of arthralgia. These molecules may be useful in treating the signs and symptoms associated with arthritis.
ISSN:1521-0103
1521-0103
DOI:10.1124/jpet.115.228932