Novel mPGES-1 inhibitor targets pain, inflammatory diseases
It has been proposed that prostaglandin E2 (PGE2), known as the principal proinflammatory prostaglandin, is implicated in pain response and also plays a role in inflammatory diseases. Particularly, the increased PGE2 level, produced by an inducible enzyme known as microsomal PGE2 synthase-1 (mPGES-1) is an indicator of pain.
University of Kentucky researchers have identified therapeutics to inhibit this pathway in order to decrease pain and inflammation. The lead compound has been tested in various mouse and rat models of inflammation, acute and chronic pain via oral administration and parenteral administration, demonstrating that the compound was effective in all of the models tested so far, including carrageenan-induced paw edema and hyperalgesia, adjuvant-induced arthritis, formalin-induced orofacial pain, neuropathic pain, and post-operative pain. None of the other mPGES-1 inhibitors reported in literature has shown better or close anti-inflammatory and analgesic effects in these animal (mouse or rat) models. In addition, the lead compound has also been tested for its acute toxicity in mice and rats, e.g. oral administration (PO) of 3 g/kg (or 3000 mg/kg) per day for 14 days, without showing any toxicity signs in any tissues or behavior. The experiments conducted include comparison studies against Celecoxib and Oxycodone. In comparison to the novel drug, a single dose of 50 mg/kg celecoxib (PO) resulted in significant toxicity (bleeding in stomach) after 24 hours.