CJ-023,423 (Grapiprant) a Potential Novel Active Compound with Antihyperalgetic Properties for Veterinary Patients

Abstract

Companion animals are now living longer and so are more commonly manifesting age- and pain-related disease. Nonsteroidal anti- inflammatory drugs are the most used drug in osteoarthritis and inflammatory pain of various aetiologies. Despite their safety profiles have been amended from the COX-non selective to the COX-2 selective inhibitor class, some adverse effects are still of concern especially in long term treatments. One prostaglandin (PG) downstream from the cyclooxygenase enzyme, PGE2, has been recognized as a pivotal mediator of pain and inflammation. The actions of PGE2 are produced by its interaction with four G-protein coupled receptors (EP1, EP2, EP3 and EP4). The EP4 receptor mediates PGE2-elicited sensitization of sensory neurons and studies have demonstrated that EP4 is a major receptor in mediating pain associated with both rheumatoid and osteoarthritis and in inflammation. CJ-023,423 (grapiprant) is a competitive antagonist of human and rat prostanoid EP4 receptors, under development for the control of pain and inflammation associated with osteoarthritisfor use in humans and dogs. A recent study has shown the good safety profile of this active ingredient in dogs. Despite this molecule is still far to be marketed because it pharmacokinetic/pharmacodynamics profile is need to be fully elucidated yet, it might be an interesting active ingredient for the veterinary medicine. activities. Two isoforms of COX, COX-1 and COX-2, have been identified. COX-1 is constitutively expressed throughout the body and it is thought to play an essential role in normal gastrointestinal and renal function, whereas COX-2 is induced in the presence of inflammation. NSAIDs inhibit both isoforms and inhibition of COX-1 is thought to cause the adverse gastrointestinal effects such as gastric erosion, ulceration and haemorrhage, whereas inhibition of COX-2 is associated with the therapeutic effects of NSAIDs. Thus, inhibition of PG synthesis by NSAIDs has demonstrated clear efficacy in the reduction of pain and inflammation and also has been shown to have putative effects beyond pain, including gastrointestinal and renal effects. These effects have been shown to be more severe in several animal species rather than in human beings (Khan and McLean, 2012). Selective COX-2 inhibitors were designed to prevent those adverse effects mediated by