Discovery of Diphenyloxazole and Nδ-Z-Ornithine Derivatives as Highly Potent and Selective Human Prostaglandin EP₄ Receptor Antagonists

Two novel classes of diphenyloxazole and Nδ-Z-ornithine derivatives as highly potent and selective EP₄ antagonists have been discovered. The optimized diphenyloxzole 8 and Nδ-Z-ornithine 11 effectively competed with [³H]PGE₂ binding to human recombinant EP₄, with K_i values of 0.30 nM and 0.91 nM, respectively, and were selective for all members of the human prostanoid receptor family. 8 was shown to exhibit good pharmacokinetic properties in rats and dogs and potent inhibitory activity toward in vitro PGE₂-promoted IgE synthesis.