title: Design, synthesis, and in vitro activity of bis(succinimido)hexane peptide heterodimers with combined B1 and B2 antagonist activity.
abstract: We have developed a series of peptide heterodimers based on the B2 antagonist D-Arg0-[Hyp3,D-Phe7,Leu8]-BK (1) and the B1 antagonist Lys0-[Leu8,des-Arg9]-BK (7) that are potent antagonists of both B1 and B2 receptors. From this series, compound 50 (alternatively, CP-0364), the 1,6-bis(succinimido)hexane heterodimer of D-Arg0-[Hyp3,Cys6,D-Phe7,Leu8]-BK (2), and D-Arg0-[Cys1,Hyp3,Leu8,des-Arg9]-BK (6), was found to be the most active both in vitro and in vivo. Compound 50 has a pA2 of 8.3 when measured against bradykinin (BK)-induced rat uterine smooth muscle contraction and an IC50 of approximately 10(-8) M against [des-Arg9]-BK-induced rabbit aorta smooth muscle contraction in vitro. Compounds such as 50 may be useful in the treatment of both subacute and chronic inflammatory disorders wherein both B2 and B1 receptors appear to contribute to the clinical manifestations of the disease.
authors.affiliation: Cortech, Incorporated, Denver, Colorado 80221.
authors.forename: J C
authors.initials: JC
authors.lastname: Cheronis
authors.forename: E T
authors.initials: ET
authors.lastname: Whalley
authors.forename: L G
authors.initials: LG
authors.lastname: Allen
authors.forename: S D
authors.initials: SD
authors.lastname: Loy
authors.forename: M W
authors.initials: MW
authors.lastname: Elder
authors.forename: M J
authors.initials: MJ
authors.lastname: Duggan
authors.forename: K L
authors.initials: KL
authors.lastname: Gross
authors.forename: J K
authors.initials: JK
authors.lastname: Blodgett
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D015195:Drug Design; D005260:Female; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014590:Uterine Contraction / Q000187:drug effects
chemical_list: D065168:Bradykinin Receptor Antagonists; D046911:Macromolecular Substances; D010455:Peptides; D001920:Bradykinin