RATIONALLY DESIGNED NON-PEPTIDES - VARIOUSLY SUBSTITUTED PIPERAZINE LIBRARIES FOR THE DISCOVERY OF BRADYKININ ANTAGONISTS AND OTHER G-PROTEIN-COUPLED RECEPTOR LIGANDS
Vs. Goodfellow et al., RATIONALLY DESIGNED NON-PEPTIDES - VARIOUSLY SUBSTITUTED PIPERAZINE LIBRARIES FOR THE DISCOVERY OF BRADYKININ ANTAGONISTS AND OTHER G-PROTEIN-COUPLED RECEPTOR LIGANDS, Molecular diversity, 2(1-2), 1996, pp. 97-102
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.