This proposal is designed to develop a potent beta-turn mimetic endothelin antagonist via directed combinatorial synthesis, and to evaluate the bioactive solution conformation of the antagonist. Endothelin, a 21 amino acid peptide, is a member of a group of important biomolecules which adopt a beta-turn conformation in solution. The proposed mimetic class contains a thioether linker to restrict the turn conformation, has three sidechains to enhance receptor binding, and has greater bioavailability than peptide antagonists. A combinatorial library will be synthesized, assayed for affinity, and the solution conformation of the strongest antagonists will be determined. A second library will then be synthesized, with components chosen to promote the probable bioactive conformer identified in the previous analysis.