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

Starting from the structure of the novel nonpeptide AT1 receptor antagonist DuP 753 (losartan), a new series of potent antagonists was designed. In these compounds the central imidazole nucleus was replaced by the dihydroimidazol-4-one structure. The most active compounds had a spirocyclopentane or a spirocyclohexane ring in position 5. Like the imidazole series, the best substituents were the linear butyl chain in position 1 and the [2'-(tetrazol-5-yl)biphenylyl]methyl group in position 3. Antagonistic activity was assessed by the ability of the compounds to competitively inhibit [125I]AII binding to the AT1 subtype receptor and to antagonize AII-induced contractions in rabbit aorta rings. The most active compounds had IC50 values in the nanomolar range. In conscious rats, compounds 4 and 21 antagonized the AII pressor response when administered orally. Compound 21 (SR 47436) was the most active; it was recently shown to also be active in cynomolgus monkeys both intravenously and orally. This molecule is now undergoing clinical trials for the treatment of hypertension.

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