Pharmacological profile of LF 16-0687, a new potent non-peptide bradykinin B2 receptor antagonist

Abstract LF 16-0687 (1-[[2,4-dichloro-3-[[(2,4-dimethylquinolin-8-yl)oxy] methyl]phenyl]sulfonyl]- N -[3-[[4-(aminoiminomethyl)phenyl] carbonylamino]propyl]-2( S )-pyrrolidinecarboxamide) has been selected from a large-scale medicinal chemistry program for further development. In competition binding studies using [ 3 H ]bradykinin (BK), LF 16-0687 bound to the human, rat and guinea-pig recombinant B 2 receptor expressed in CHO cells giving K i values of 0.67 nM, 1.74 nM and 1.37 nM, respectively. It also bound to the native BK B 2 receptor from human umbilical vein (HUV), rat uterus (RU) and guinea-pig ileum (GPI) giving K i values of 0.89 nM, 0.28 nM and 0.98 nM, respectively. It inhibited BK-induced IP1, IP2 and IP3 formation in INT407 cells yielding p K B values of 8.5, 8.6 and 8.7, respectively. In isolated organs experiments, LF 16-0687 behaved as a competitive antagonist of BK-mediated contractions giving p A 2 values of 9.1 in HUV, 7.7 in RU and 9.1 in GPI. Binding and functional studies performed over 40 different receptors revealed that LF 16-0687 was selective for the BK B 2 receptor. A continuous intravenous infusion of LF 16-0687 antagonized in a dose-dependent manner and with a rapid onset of action BK-induced hypotensive response. Subcutaneous administration of LF 16-0687 at 1.1 μmol/kg to rats markedly reduced BK-induced edema of the stomach (−69%), duodenum (−65%) and pancreas (−56%).