As we all know, Colitis is a kind of inflammatory diseases. Sometimes it is acute and long term, makes patients painful.
EP4 receptor (Prostaglandin E2 receptor 4) is a prostaglandin receptor for prostaglandin E2. It is one of EP receptors, in addition to EP1, EP2, and EP3. The receptor exhibits high levels in the small intestine and colon. As a result, EP4 receptor seems to exhibit anti-inflammatory activity. Activation of this receptor may be useful in treatment of inflammatory diseases. Thus, agonists of EP4 receptor become a hot spot in the research of inflammation.
Additionally, in recent years, researchers discovered a series of compounds targeting EP4. Yusuke Watanabe, et al found out a potent EP4 receptor agonist, KAG-308, with excellent anti-ulcerative colitis activity.
On one hand, KAG-308 selective binds to human EP4 receptor, with a Ki value of 2.57 nM. It shows much more selectivity over human EP1, EP2, EP3, and IP, with Kis of 1410, 1540, 32.4, and 52.9 nM, respectively. Furthermore, KAG-308 displays significant agonistic activity for human EP4, weak activity for human EP1, EP2, EP3. The corresponding Ki values are 17, 1000, 1000, 160 nM.
On the other hand, KAG-308 potently and dose-dependently inhibits TNF-α production in LPS-stimulated peripheral whole blood and anti-CD3/CD28 stimulated CD4þ T cells.
Besides, KAG-308 exhibits anti-colitis activity in vivo. It is orally active. KAG-308 prevents colorectal carcinogenesis through inhibition of colitis development and decreasing mortality in a colitis-associated cancer model.
References:
1. Watanabe Y, et al. Eur J Pharmacol. 2015 May 5;754:179-89.