The identification of an orally active, nonpeptide bradykinin B2 receptor antagonist, FR173657.
1. An orally active, nonpeptide bradykinin (BK) B2 receptor antagonist, FR173657 (E)-3-(6-acetamido-3-pyridyl)-N-[N-[2-4-dichloro-3-[(2-methyl-8-quinolin yl) oxymethyl]phenyl]-N-methylaminocarbonyl-methyl] acrylamide) has been identified. 2. This compound displaced [3H]-BK binding to B2 receptors present in guinea-pig ileum membranes with an IC50 of 5.6 x 10(-10) M and in rat uterus with an IC50 of 1.5 x 10(-9) M. It did not inhibit different specific radio-ligand binding to other receptor sites. 3. In human lung fibroblast IMR-90 cells, FR173657 displaced [3H]-BK binding to B2 receptors with an IC50 of 2.9 x 10(-9) M and a Ki of 3.6 x 10(-10) M, but did not reduce [3H]-des]Arg10-kallidin binding to B1 receptors. 4. In guinea-pig isolated preparations, FR173657 antagonized BK-induced contractions with an IC50 of 7.9 x 10(-9) M, but did not antagonize acetylcholine or histamine-induced contractions even at a concentration of 10(-6) M. FR173657 caused parallel rightward shifts of the concentration-response curves to BK at concentrations of 10(-9) M and 3.2 x 10(-9) M, and a little depression of the maximal response in addition to the parallel rightward shift of the concentration-response curve at a concentration of 10(-8) M. Analysis of the data yield a pA2 of 9.2 +/- 0.2 (n = 5) and a slope of 1.5 +/- 0.2 (n = 5). 5. In vivo, the oral administration of FR173657 inhibited BK-induced bronchoconstriction dose-dependently in guinea-pigs with an ED50 of 0.075 mg kg-1, but did not inhibit histamine-induced bronchoconstriction even at 1 mg kg-1. FR173657 also inhibited carrageenin-induced paw oedema with an ED50 of 6.8 mg kg-1 2 h after the carrageenin injection in rats. 6. These results show that FR173657 is a potent, selective, and orally active bradykinin B2 receptor antagonist.
Asano
M
M
Department of Pharmacology, Fujisawa Pharmaceutical Co, Ltd., Ibaraki, Japan.
Inamura
N
N
Hatori
C
C
Sawai
H
H
Fujiwara
T
T
Katayama
A
A
Kayakiri
H
H
Satoh
S
S
Abe
Y
Y
Inoue
T
T
Sawada
Y
Y
Nakahara
K
K
Oku
T
T
Okuhara
M
M
D000284:Administration, Oral; D000818:Animals; D001920:Bradykinin / Q000037:antagonists & inhibitors; D065168:Bradykinin Receptor Antagonists; D016084:Bronchoconstriction / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000517:prevention & control; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D011804:Quinolines / Q000008:administration & dosage* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000378:metabolism; D014599:Uterus / Q000378:metabolism
D065168:Bradykinin Receptor Antagonists; C105311:FR 173657; D011804:Quinolines; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D001920:Bradykinin