title: 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 B1 receptor: 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)-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 [(3)H]Lys(0)-des-Arg(9)-BK to the B(1) receptor in human fibroblast MRC5 and to recombinant human B(1) receptor expressed in human embryonic kidney cells with inhibition constants (K(i)) of 0.48 and 0.73 nM, respectively. 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 8.9 and 9.4, respectively. Antagonistic properties of SSR240612 were also demonstrated in vivo. SSR240612 inhibited des-Arg(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.
authors.affiliation: Sanofi-Synthelabo Recherche, Montpellier, France. jean.gougat@sanofi-synthelabo.com
authors.forename: Jean
authors.initials: J
authors.lastname: Gougat
authors.forename: Bernard
authors.initials: B
authors.lastname: Ferrari
authors.forename: Lionel
authors.initials: L
authors.lastname: Sarran
authors.forename: Claudine
authors.initials: C
authors.lastname: Planchenault
authors.forename: Martine
authors.initials: M
authors.lastname: Poncelet
authors.forename: Jeanne
authors.initials: J
authors.lastname: Maruani
authors.forename: Richard
authors.initials: R
authors.lastname: Alonso
authors.forename: Annie
authors.initials: A
authors.lastname: Cudennec
authors.forename: Tiziano
authors.initials: T
authors.lastname: Croci
authors.forename: Fabio
authors.initials: F
authors.lastname: Guagnini
authors.forename: Katalin
authors.initials: K
authors.lastname: Urban-Szabo
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Martinolle
authors.forename: Philippe
authors.initials: P
authors.lastname: Soubrié
authors.forename: Olivier
authors.initials: O
authors.lastname: Finance
authors.forename: Gérard
authors.initials: G
authors.lastname: Le Fur
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D065169:Bradykinin B1 Receptor Antagonists; D016466:CHO Cells; D006224:Cricetinae; D004149:Dioxoles / Q000494:pharmacology*; D004195:Disease Models, Animal; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005557:Formaldehyde; D006801:Humans; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C487113:2-((3-(1,3-benzodioxol-5-yl)-3-(((6-methoxy-2-naphthyl)sulfonyl)amino)propanoyl)amino)-3-(4-((2,6-dimethylpiperidinyl)methyl)phenyl)-N-isopropyl-N-methylpropanamide; D000700:Analgesics; D065169:Bradykinin B1 Receptor Antagonists; D004149:Dioxoles; D013449:Sulfonamides; D005557:Formaldehyde