title: Rationally designed non-peptides: variously substituted piperazine libraries for the discovery of bradykinin antagonists and other G-protein-coupled receptor ligands.
abstract: Molecular modeling studies of potent decapeptide bradykinin antagonists 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 approximately 55 microM) on a cloned human B2 receptor and antagonist activity in an in vitro human-cell functional assay. The success of these structures led to the creation of prototype libraries based on variously substituted 1,4-piperazine scaffolds, which allowed a rapid and general search of pharmacophores 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-substituted structures, and the adaptation of simultaneous ring closure and resin cleavage to drive the formation of highly hindered amide bonds. Using this chemistry, a rationally directed non-peptide library of approximately 2500 N,N'-disubstituted piperazines and piperazinediones was synthesized and screened for ligand affinity on bradykinin, neurokinin, and opioid receptors. A number of lead structures were identified. Notably, a bradykinin antagonist lead, CP-2458, with good receptor selectivity and antagonist activity in human-cell assays was identified and is undergoing optimization by traditional and combinatorial methods.
authors.affiliation: Department of New Leads Chemistry, Cortech Inc., Denver, CO 80221, USA.
authors.forename: V S
authors.initials: VS
authors.lastname: Goodfellow
authors.forename: C P
authors.initials: CP
authors.lastname: Laudeman
authors.forename: J I
authors.initials: JI
authors.lastname: Gerrity
authors.forename: M
authors.initials: M
authors.lastname: Burkard
authors.forename: E
authors.initials: E
authors.lastname: Strobel
authors.forename: J S
authors.initials: JS
authors.lastname: Zuzack
authors.forename: D A
authors.initials: DA
authors.lastname: McLeod
mesh_terms: D000107:Acetylation; D017607:Aluminum Compounds; D000588:Amines / Q000737:chemistry; D001920:Bradykinin / Q000037:antagonists & inhibitors*; D002851:Chromatography, High Pressure Liquid; D015195:Drug Design; D019204:GTP-Binding Proteins / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D018020:Lithium Compounds; D008958:Models, Molecular; D019151:Peptide Library; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000737:chemistry*; D019163:Reducing Agents; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D017607:Aluminum Compounds; D000588:Amines; D008024:Ligands; D018020:Lithium Compounds; D019151:Peptide Library; D010879:Piperazines; D011956:Receptors, Cell Surface; D019163:Reducing Agents; C042073:lithium aluminum hydride; D019204:GTP-Binding Proteins; D001920:Bradykinin