Platelet Activating Factor Antagonists

Platelet Activating Factor (PAF) is a D-glycerol-derived phospholipid which is a potent endogenous mediator of inflammation. PAF is synthesized and released by a variety of cell types and elicits its biological activity by interacting with specific G-protein coupled receptors found on platelets, neutrophils, and other inflammatory cells. The physiological consequences of the interaction of PAF with its receptor includes an increase in vascular permeability, hypotension, bronchoconstriction, and platelet and neutrophil aggregation. These biological effects are consistent with the concept that PAF is involved in a number of inflammatory diseases such as septic shock and asthma. Given the potent pathophysiological effects of PAF, a great deal of effort has been focused on the discovery of agents which block the action of PAF at its receptor. Within the past 10 years, a wide range of structures have been identified as PAF antagonists. These include not only PAF analogs, but also antagonists derived from natural products as well as non-lipid synthetic compounds. Several theories have been proposed to unify these diverse structural classes, but sophisticated molecular models of the receptor have not been widely employed. The discovery of new PAF antagonists has relied heavily on traditional medicinal chemistry approaches. A number of PAF antagonists have advanced to clinical evaluation. While several early compounds demonstrated efficacy in animal models of asthma they have failed to provide benefit for this condition in man. The current generation of potent antagonists are being evaluated as therapies for sepsis, pancreatitis and other disorders.