title: Pharmacological profile of LF 16-0687, a new potent non-peptide bradykinin B2 receptor antagonist.
abstract: LF 16-0687 (1-[[2,4-dichloro-3-[[(2,4-dimethylquinolin-8-yl)oxy] methyl]phenyl]sulfonyl]-N-[3-[[4-(aminoimethyl) phenyl] carbonylamino]propyl]-2(S)-pyrrolidinecarboxamide) has been selected from a large-scale medicinal chemistry program for further development. In competition binding studies using [3H]bradykinin (BK), LF 16-0687 bound to the human, rat and guinea-pig recombinant B2 receptor expressed in CHO cells giving K(i) values of 0.67 nM, 1.74 nM and 1.37 nM, respectively. It also bound to the native BK B2 receptor from human umbilical vein (HUV), rat uterus (RU) and guinea-pig ileum (GPI) giving K(i) values of 0.89 nM, 0.28 nM and 0.98 nM, respectively. It inhibited BK-induced IP1, IP2 and IP3 formation in INT407 cells yielding pK(B) values of 8.5, 8.6 and 8.7, respectively. In isolated organs experiments, LF 16-0687 behaved as a competitive antagonist of BK-mediated contractions giving pA2 values of 9.1 in HUV, 7.7 in RU and 9.1 in GPI. Binding and functional studies performed over 40 different receptors revealed that LF 16-0687 was selective for the BK B2 receptor. A continuous intravenous infusion of LF 16-0687 antagonized in a dose-dependent manner and with a rapid onset of action BK-induced hypotensive response. Subcutaneous administration of LF 16-0687 at 1.1 micromol/kg to rats markedly reduced BK-induced edema of the stomach (- 69%), duodenum (-65%) and pancreas (-56%).
authors.affiliation: Centre de Recherche, Laboratoires Fournier, Daix, France. d.pruneau@fournier.fr
authors.forename: D
authors.initials: D
authors.lastname: Pruneau
authors.forename: J L
authors.initials: JL
authors.lastname: Paquet
authors.forename: J M
authors.initials: JM
authors.lastname: Luccarini
authors.forename: E
authors.initials: E
authors.lastname: Defrêne
authors.forename: C
authors.initials: C
authors.lastname: Fouchet
authors.forename: R M
authors.initials: RM
authors.lastname: Franck
authors.forename: B
authors.initials: B
authors.lastname: Loillier
authors.forename: C
authors.initials: C
authors.lastname: Robert
authors.forename: P
authors.initials: P
authors.lastname: Bélichard
authors.forename: H
authors.initials: H
authors.lastname: Duclos
authors.forename: B
authors.initials: B
authors.lastname: Cremers
authors.forename: P
authors.initials: P
authors.lastname: Dodey
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001812:Blood-Brain Barrier; D065168:Bradykinin Receptor Antagonists; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043782:Receptor, Bradykinin B2
chemical_list: D065168:Bradykinin Receptor Antagonists; D007295:Inositol Phosphates; C403051:LF 16-0687; D011804:Quinolines; D043782:Receptor, Bradykinin B2