Pharmacological profile of LF 16-0687, a new potent non-peptide bradykininB-2 receptor antagonist

LF 16-0687 (1-[[2,4-dichloro-3-[[(2,4-dimethylquinolin-8-yl)oxy] methyl]phe nyl]sulfonyl]-N-[3-[[4-(aminoiminomethyl)-phenyl] carbonylamino]propyl]-2(S )-pyrrolidinecarboxamide) has been selected from a large-scale medicinal ch emistry program for further development. In competition binding studies usi ng [H-3]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 n M, 1.74 nM and 1.37 nM, respectively. It also bound to the native BK B-2 re ceptor from human umbilical vein (HUV), rat uterus (RU) and guinea-pig ileu m (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 experimen ts, LF 16-0687 behaved as a competitive antagonist of BK-mediated contracti ons giving pA(2) values of 9.1 in HUV, 7.7 in RU and 9.1 in GPI, Binding an d functional studies performed over 40 different receptors revealed that LF 16-0687 was selective for the BK Bz receptor. A continuous intravenous inf usion of LF 16-0687 antagonized in a dose-dependent manner and with a rapid onset of action BK-induced hypotensive response. Subcutaneous administrati on of LF 16-0687 at 1.1 mu mol/kg to rats markedly reduced BK-induced edema of the stomach (- 69%), duodenum (- 65%) and pancreas (- 56%). (C) 1999 El sevier Science B.V. All rights reserved.