Abstract

The biochemical and pharmacological properties of a novel non-peptide antagonist of the bradykinin (BK) B₁ receptor, SSR240612 [(2R)-2-[((3R)-3-(1,3-benzodioxol-5-yl)-3-{[(6-methoxy-2-naphthyl)sulfonyl]amino}propanoyl)amino]-3-(4-{[2R,6S)-2,6-dimethylpiperidinyl]methyl}phenyl)-N-isopropyl-N-methylpropanamide hydrochloride] were evaluated. SSR240612 inhibited the binding of [³H]Lys⁰-des-Arg⁹-BK to the B₁ receptor in human fibroblast MRC5 and to recombinant human B₁ receptor expressed in human embryonic kidney cells with inhibition constants (K_i) of 0.48 and 0.73 nM, respectively. The compound selectivity for B₁ versus B₂ receptors was in the range of 500- to 1000-fold. SSR240612 inhibited Lys⁰-desAr⁹-BK (10 nM)-induced inositol monophosphate formation in human fibroblast MRC5, with an IC₅₀ of 1.9 nM. It also antagonized des-Arg⁹-BK-induced contractions of isolated rabbit aorta and mesenteric plexus of rat ileum with a pA₂ of 8.9 and 9.4, respectively. Antagonistic properties of SSR240612 were also demonstrated in vivo. SSR240612 inhibited des-Arg⁹-BK-induced paw edema in mice (3 and 10 mg/kg p.o. and 0.3 and 1 mg/kg i.p.). Moreover, SSR240612 reduced capsaicin-induced ear edema in mice (0.3, 3 and 30 mg/kg p.o.) and tissue destruction and neutrophil accumulation in the rat intestine following splanchnic artery occlusion/reperfusion (0.3 mg/kg i.v.). The compound also inhibited thermal hyperalgesia induced by UV irradiation (1 and 3 mg/kg p.o.) and the late phase of nociceptive response to formalin in rats (10 and 30 mg/kg p.o.). Finally, SSR240612 (20 and 30 mg/kg p.o.) prevented neuropathic thermal pain induced by sciatic nerve constriction in the rat. In conclusion, SSR240612 is a new, potent, and orally active specific non-peptide bradykinin B₁ receptor antagonist.