DESIGN, SYNTHESIS, AND IN-VITRO ACTIVITY OF BIS(SUCCINIMIDO)HEXANE PEPTIDE HETERODIMERS WITH COMBINED B-1 AND B-2 ANTAGONIST ACTIVITY

We have developed a series of peptide heterodimers based on the B-2 antagonist D-Arg(0)-[Hyp(3),D-Phe(7),Leu(8)]-BK (1) and the B-1 antagonist Lys(0)-[Leu(8),des-Arg(9)]-BK (7) that are potent antagonists of both B-1 and B-2 receptors. From this series, compound 50 (alternatively, CP-0364), the 1,6-bis (succinimido)hexane heterodimer of D-Arg(0)-[Hyp(3),Cys(6),D-Phe(7),Leu(8)]-BK (2), and D-Arg(0)-[Cys(1),-Hyp(3),Leu(8),des-Arg(9)] -BK (6),was found to be the most active both in vitro and in vivo. Compound 50 has a pA(2) of 8.3 when measured against bradykinin (BK)-induced rat uterine smooth muscle contraction and an IC50 of approximately 10(-8) M against [des-Arg(9)] -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 B-2 and B-1 receptors appear to contribute to the clinical manifestations of the disease.