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Abstract
Prostaglandin (PG) E2 is the key driver of inflammation associated with arthritic conditions. Inhibitors of PGE 2 production (NSAIDs and Coxibs) are used to treat these conditions, but carry significant side effect risks due to the inhibition of all prostanoids that play important physiological function. The activities of PGE 2 are transduced through various receptor sub‐types. Prostaglandin E2 type 4 receptor (EP4) is associated with the development of inflammation and autoimmunity. We therefore are interested in identifying novel EP4 antagonists to treat the signs and symptoms of arthritis without the potential side effects of PGE 2 modulators such as NSAIDs and Coxibs. Novel EP4 antagonists representing distinct chemical scaffolds were identified using a variety of in vitro functional assays and were shown to be selective and potent. The compounds were shown to be efficacious in animal models of analgesia, inflammation, and arthritis.
Highlights
Chronic inflammation of the synovial joint is a common feature of both osteoarthritis (OA) and rheumatoid arthritis (RA) and is associated with pain, swelling, synovial hyperplasia, destruction of cartilage and bone, leading to reduced mobility (Gardner 1994; Sokolove and Lepus 2013)
Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics
The molecules were effective in alleviating pain and inflammation associated with rat MIA and adjuvant induced arthritis (AIA)
Summary
Chronic inflammation of the synovial joint is a common feature of both osteoarthritis (OA) and rheumatoid arthritis (RA) and is associated with pain, swelling, synovial hyperplasia, destruction of cartilage and bone, leading to reduced mobility (Gardner 1994; Sokolove and Lepus 2013). Multiple prostaglandins are produced, PGE2 is the most prominent prostanoid responsible for the inflammation and pain in both OA and RA. In animal models of arthritis, a neutralizing antibody to PGE2 is as effective as nonsteroidal anti-inflammatory drugs (NSAIDs) treatment (Portanova et al 1996) in reducing inflammation and hyperalagesia. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.
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