deCODE chemistry

A review.Current antiplatelet therapies offer significant benefits for the treatment of patients at risk for recurrent cardiovascular events.However, clin. data suggest that many of these agents lead to an increased risk of severe or fatal hemorrhage by affecting general platelet function.It has been suggested that targeting the inflammatory component of the disease instead may address this issue.Human genetic data from peripheral arterial occlusive disease (PAOD), heart attack and stroke converged on the identification of the EP₃ receptor as a target, linking variations in the gene encoding EP₃ to an increased risk for the disease.Several small-mol. EP₃ antagonists employed either as monotherapy or in combination with clopidogrel and aspirin have been shown to inhibit platelet aggregation at the site of lesions in the vasculature, without increasing bleeding time.This suggests that targeting the inflammatory mechanism of arterial thrombosis mediated by the prostaglandin E₂ (PGE₂)-EP₃ receptor system may lead to a new generation of anti-platelet drugs with an enhanced safety and efficacy profile.

Development of compounds as antagonist for one of a family of highly homologous receptors continues to be a major challenge.The EP3 receptor is one of the four related GPCR receptors (EP1-EP4) that bind prostaglandin E2 (PGE2).EP3 is expressed on platelets and mediates PGE2 amplified platelet aggregation.Here we describe the synthesis, structure-activity relationships (SAR) and biol. evaluation of a series of 3,4-disubstituted oxyindoles which show potent antagonistic activity against the human EP3 receptor and high selectivity vs. other prostanoid receptors-other human EP receptor family members (hEP1, hEP2, hEP4) and the human FP and IP receptors.

deCODE has identified variations in the gene encoding EP3 that confer significantly increased risk for the most severe forms of peripheral arterial occlusive disease (PAOD).The disease is estimated to effect 12-20 percent of Americans age 65 years of age or older (perhaps 8 to 12 million persons in total).During this presentation, highlights of our medicinal chem. approach which incorporates in-vitro ADMET tools to identify barriers earlier during lead generation and SAR generation phase will be described.The evolution of this medicinal chem. directed program led to the identification of DG-041 as a potent, selective, orally bioavailable small mol. development candidate for the prostanoid EP3 receptor.Highlights of the SAR and pre-clin. characteristics describing DG-041 as a novel anti-platelet agent will be presented.