The synthesis of nonpeptidic alpha-helix mimetics based on a tricyclic oxazole-pyrrole-piperazine scaffold is described. The scaffold presents both a hydrophobic surface for recognition and a hydrophilic edge that enhances solubility. The synthesis is highly modular and allows the targeting of a range of protein-protein interactions involving a-helices. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008).