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], a New Nonpeptide Antagonist of the Bradykinin B₁Receptor: Biochemical and Pharmacological Characterization

Abstract

The biochemical and pharmacological properties of a novel non-peptide antagonist of the bradykinin (BK) B 1 receptor, SSR240612 [(2R)-2-[((3R)The compound selectivity for B 1 versus B 2 receptors was in the range of 500-to 1000-fold. SSR240612 inhibited Lys 0 -desAr 9 -BK (10 nM)-induced inositol monophosphate formation in human fibroblast MRC5, with an IC 50 of 1.9 nM. It also antagonized des-Arg 9 -BK-induced contractions of isolated rabbit aorta and mesenteric plexus of rat ileum with a pA 2 of 8.9and 9.4, respectively. Antagonistic properties of SSR240612 were also demonstrated in vivo. SSR240612 inhibited desArg 9 -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 B 1 receptor antagonist.Kinins are 9 to 11 amino acid peptides known to be important mediators of pain, inflammation, and cardiovascular homeostasis. They are released in injured tissues from kininogen by activation of plasma or tissue kallikreins (Bhoola et al., 1992). Kinins exert their biological activities via the activation of two subtypes of G-protein coupled receptors, denoted B 1 and B 2 receptors (Regoli and Barabe, 1980;Regoli et al., 1998). Bradykinin (BK) and Lys 0 -BK are natural endogenous agonists of bradykinin B 2 receptors, whereas their kininase I-hydrolyzed metabolites des-Arg 9 -BK and Lys 0 -des-Arg 9 -BK are specific agonists of bradykinin B 1 receptors. B 1 peptide antagonists were obtained by replacing the C-terminal Phe residue of agonists by Leu. Human and rabbit B 1 receptors have a higher affinity for Lys 0 -desArticle, publication date, and citation information can be found at

Reduced Nerve Injury-Induced Neuropathic Pain in Kinin B1Receptor Knock-Out Mice

“…Thus, the activation of B 1 receptors is a critical step in the production of neuropathic pain, and B 1 receptor blockade is able to not only prevent the development of nociception but also reduce an established painful condition. phenyl)-N-isopropyl-N-methylpropanamide hydrochloride] was able to reduce the thermal hyperalgesia produced by sciatic nerve injury in rats (Gougat et al, 2004). These findings support the notion that the development of oral-selective B 1 receptor antagonists might be expected to have clinical therapeutic potential in the management of neuropathic pain.…”

“…Increased levels of B 1 and B 2 receptor mRNA or protein have been found in dorsal root ganglia (DRGs) after sciatic nerve constriction in rats and mice (Petersen et al, 1998;Eckert et al, 1999;Levy and Zochodne, 2000;Yamaguchi-Sase et al, 2003;Rashid et al, 2004). Of note, the systemic administration of B 1 or B 2 receptor antagonists has been found to reduce thermal hyperalgesia and mechanical allodynia produced by sciatic nerve constriction in rats (Levy and Zochodne, 2000;Yamaguchi-Sase et al, 2003;Gougat et al, 2004). Plasma seems to be the main source of endogenous kinins after nerve injury, and there is recent evidence demonstrated that neuropathic pain is reduced in mutant plasma kininogen-deficient B/N-Katholiek rats when compared with normal B/N-Kitasato rats (Yamaguchi-Sase et al, 2003).…”

Neuropathic Pain-Like Behavior after Brachial Plexus Avulsion in Mice: The Relevance of Kinin B1and B2Receptors

“…The doses of the R-715 and SSR240612 were selected on the basis of literature data or pilot experiments (Gobeil et al, 1996;Fernandes et al, 2003;Gougat et al, 2004). Under these protocols of treatment, neither the R-715 nor the SSR240612 altered the basal threshold response of animals.…”

Selective Kinin Receptor Agonists as Cardioprotective Agents in Myocardial Ischemia and Diabetes

“…, 300 mg/kg kindly provided by J. Gougat, Sanofi, Montpellier, France) (Gougat et al, 2004), 5 minutes before the onset of ischemia.…”