Compounds targeting multiple prostanoid receptors

Abstract

The prostanoids are a large family of oxygenated fatty acids that mediate numerous biological effects. They are biosynthesized from arachidonic acid by the enzymes cyclo-oxygenase-1 and -2 and inhibitors of these enzymes are widely indicated as drugs for treating inflammation, pain, and fever. Following structural elucidation of the pharmacologically defined prostanoid receptors, drug design largely switched from COX inhibitors to pharmacology. Potent and selective antagonists for each of the prostanoid receptors (DP 1-2 , EP 1-4 , FP, IP, TP) were developed but these have not translated into widely used new drugs, despite the clear importance of prostanoids in disease. Responding to this situation, a new polypharmacological approach was adopted whereby multiple activities were embodied in a single molecule. The receptors selected for antagonism were selected based on known roles in mediating inflammation and fibrosis. Receptors opposing pro-inflammatory events, notably EP 2 , were left open so that PGE 2 may be converted from a pro-inflammatory to an endogenously released anti-inflammatory mediator. This resulted in compounds with greater anti-inflammatory efficacy than antagonists selective for a single prostanoid receptor and cyclo-oxygenase inhibitors. Next steps in the