A specific new EP4 receptor antagonist for Rheumatoid Arthritis
Rheumatoid arthritis (RA) and osteoarthritis (OA) are chronic diseases that cause joint pain, swelling, cartilage and bone destruction, and joint stiffness. They are both forms of arthritis but have different causes and treatments. Both RA and OA involve chronic inflammation in the joints, with synovial hyperplasia, but the inflammation symptoms in RA are much greater because it is driven by autoimmune mechanisms. There is currently no efficient cure for RA, but various treatments can help manage pain symptoms, improve people’s quality of life, and slow down the condition’s progression.
The most frequently used medications are still nonsteroidal anti-inflammatory drugs (NSAIDs) that reduce inflammation symptoms. These molecules act as inhibitors of the prostanoid cascade, which plays a key role in inflammation onset and propagation. Like all other molecules targeting generic biological pathways, NSAIDs act by blocking the overall production of bioactive mediators called prostaglandins (PG). The activity of all prostanoid receptors binding PG is impaired, possibly leading to a wide variety of side effects beyond the expected beneficial outcomes.
In this article, Srinivasan Chandrasekhar describes the full pharmacological profiles of a new, potent and selective EP4 receptor antagonist series. Compound profiles, selectivity, and profiling are first run on EP4 receptor HEK transfected cells through cAMP quantification. The most promising scaffolds are then studied closely in a panel of other in-vitro assays, including off-target activity panels, TNFα measurement from whole blood. Lastly, they are assessed in-vivo on a large set of animal models for diseases.
The willow tree was used thousands of years ago as a medicine by ancient civilizations such as Sumerians and Egyptians. It contains an active substance that acts as an anti-inflammatory or analgesic for non-specific pain. This is the genesis of aspirin, still widely used today. In the 21st century, modern science is still on-track to identify new generations of more potent and selective anti-inflammatory drugs!
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
Pharmacology Research & Perspectives. 2017 May 14;5(3): e00316.