Aminopyrazole derivatives constitute the first class of nonpeptidic rationally designed
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-sheet ligands.Here we describe a double solid-phase protocol for both synthesis and affinity testing. The presentedsolid-phase synthesis of four types of hybrid compounds relies on the Fmoc strategy and circumventssubsequent HPLC purification by precipitating the final product from organic solution in pure form.Hexa- and octapeptide pendants with internal di- and tetrapeptide bridges are now amenable in highyields to combinatorial synthesis of compound libraries for high-throughput screening purposes. Solid-phase peptide synthesis (SPPS) on an acid-resistant PAM allows us, after PMB deprotection, to subjectthe free aminopyrazole binding sites in an immobilized state to on-bead assays with fluorescence-labeledpeptides. From the fluorescence emission intensity decrease, individual binding constants can be calculatedvia reference curves by simple application of the law of mass action. Gratifyingly, host/guest complexationcan be monitored quantitatively even for those ligands, which are almost insoluble in water.