SSR240612

SSR240612 is a potent and orally active specific non-peptide bradykinin B1 receptor antagonist (Kis = 0.48-0.73 and 358-481 nM for B1 and B2 receptors respectively) . (In Vitro) :SSR240612 is a potent bradykinin B1 receptor antagonist, with Kis of 0.48 nM and 0.73 nM for B2 kinin receptors of human fibroblast MRC5 and HEK cells expressing human B1 receptors, 481 nM and 358 nM for B1 receptors of guinea pig ileum membranes and CHO cells expressing human B1 receptor, respectively. SSR240612 inhibits inositol phosphate 1 formation with an IC50 of 1.9 nM, but shows no obvious effect on inositol phosphate-1 formation induced by BK (3 nM) activation of B2 receptor in human fibroblast MRC5. (In Vivo) :SSR240612 (10 mg/kg p.o. or 0.3, 1 mg/kg i.p.) obviously blocks the des-Arg9-BK-induced paw edema in the mice. SSR240612 (10 and 30 mg/kg) reduces the duration of the late phase of paw licking in a dose dependent manner in the formalin model of inflammation in mice. SSR240612 (0.3, 3, and 30 mg/kg, p.o.) treatment before capsaicin potently and non-concentration-dependently reduces the ear edema. SSR240612 (0.3 mg/kg, i.v.) also suppresses the tissue destruction and neutrophil accumulation in the rat intestine, after splanchnic artery occlusion/reperfusion. Moreover, SSR240612 (1 and 3 mg/kg p.o.) dramacally increases the withdrawal latencies in the thermal hyperalgesia induced by UV irradiation in rats. SSR240612 inhibits tactile and cold allodynia at 3 h in glucose-fed rats but had no effect in control rats with ID50s of 5.5 and 7.1 mg/kg, respectively. SSR240612 shows no effect on plasma glucose and insulin, insulin resistance (HOMA index) and aortic superoxide anion production in glucose-fed rats at 10 mg/kg.