PT - JOURNAL ARTICLE AU - Gougat, Jean AU - Ferrari, Bernard AU - Sarran, Lionel AU - Planchenault, Claudine AU - Poncelet, Martine AU - Maruani, Jeanne AU - Alonso, Richard AU - Cudennec, Annie AU - Croci, Tiziano AU - Guagnini, Fabio AU - Urban-Szabo, Katalin AU - Martinolle, Jean-Pierre AU - Soubrié, Philippe AU - Finance, Olivier AU - Le Fur, Gérard TI - SSR240612 [(2<em>R</em>)-2-[((3<em>R</em>)-3-(1,3-Benzodioxol-5-yl)-3-{[(6-methoxy-2-naphthyl)sulfonyl]amino}propanoyl)amino]-3-(4-{[2<em>R</em>,6<em>S</em>)-2,6-dimethylpiperidinyl]methyl}phenyl)-<em>N</em>-isopropyl-<em>N</em>-methylpropanamide Hydrochloride], a New Nonpeptide Antagonist of the Bradykinin B<sub>1</sub> Receptor: Biochemical and Pharmacological Characterization AID - 10.1124/jpet.103.059527 DP - 2004 May 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 661--669 VI - 309 IP - 2 4099 - http://jpet.aspetjournals.org/content/309/2/661.short 4100 - http://jpet.aspetjournals.org/content/309/2/661.full SO - J Pharmacol Exp Ther2004 May 01; 309 AB - 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 (Ki) 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. The American Society for Pharmacology and Experimental Therapeutics