RATIONALLY DESIGNED NON-PEPTIDES - VARIOUSLY SUBSTITUTED PIPERAZINE LIBRARIES FOR THE DISCOVERY OF BRADYKININ ANTAGONISTS AND OTHER G-PROTEIN-COUPLED RECEPTOR LIGANDS

Molecular modeling studies of potent decapeptide bradykinin antagonist s suggested the de novo design of peptide mimetics based on a 1,2,3,4- tetrasubstituted 1,4-piperazin-6-one scaffold. These de novo-designed antagonists exhibited only modest potency (IC50 similar to 55 mu M) on a cloned human B-2 receptor and antagonist activity in an in vitro hu man-cell functional assay. The success of these structures led to the creation of prototype libraries based on variously substituted 1,4-pip erazine scaffolds, which allowed a rapid and general search of pharmac ophores attached to a piperazine scaffold. The parent piperazinedione structures and fully reduced piperazine libraries differ from recently reported diketopiperazine libraries in the use of diverse nonnatural amino acids, on-resin-submonomer synthesis to provide more diverse N-s ubstituted structures, and the adaptation of simultaneous ring closure and resin cleavage to drive the formation of highly hindered amide bo nds. Using this chemistry, a rationally directed non-peptide library o f approximately 2500 N,N'-disubstituted piperazines and piperazinedion es was synthesized and screened for ligand affinity on bradykinin, neu rokinin, and opioid receptors. A number of lead structures were identi fied. Notably, a bradykinin antagonist lead, CP-2458, with good recept or selectivity and antagonist activity in human-cell assays was identi fied and is undergoing optimization by traditional and combinatorial m ethods.