Yuki Sawada

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‐quinolinyl) 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 × 10−10 M and in rat uterus with an IC50 of 1.5 × 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 × 10−9 M and a Ki of 3.6 × 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 × 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 × 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.

Pharmacological characterization of a nonpeptide bradykinin B2 receptor antagonist, FR165649, and agonist, FR190997.

The nonpeptide bradykinin (BK) B2 receptor antagonist, FR165649 (8‐[2,6‐dichloro‐3‐[N‐[(E)‐4‐(N‐ methylcarbamoyl)cinnamidoacetyl] ‐N‐methylamino] benzyloxy] ‐2 ‐ methylquinoline), and agonist, FR190997 (8‐[2,6‐dichloro‐3‐[N‐[(E)‐4‐(N‐methylcarbamoyl) cinnamidoacetyl]‐N‐methylamino]benzyloxy]‐2‐methyl‐4‐(2‐pyridylmethoxy)quinoline) have been identified. These compounds have a common chemical structure, and the 2‐pyridylmethoxy group is the only structural difference between them. Both FR165649 and FR190997 displaced [3H]‐BK binding to B2 receptors in guinea‐pig ileum membranes, with an IC50 of 4.7×10−10 M and 1.5×10−9 M, respectively. They also displaced [3H]‐BK binding to B2 receptors in human lung fibroblast IMR‐90 cells, with an IC50 of 1.6×10−9 M and 9.8×10−10 M, respectively. In guinea‐pig isolated ileum‐preparations, FR165649 had no agonistic effect on contraction and caused parallel rightward shifts of the concentration‐response curves to BK on contraction. Analysis of the data produced a nominal pA2 value of 9.2±0.1 (n=5) and a slope of 1.4±0.1 (n=5). On the other hand, FR190997 induced concentration‐dependent contraction of guinea‐pig ilea with a pD2 of 7.9±0.2 and the contraction was inhibited by a specific peptide bradykinin B2 receptor antagonist, Hoe 140 (D‐Arg‐[Hyp3, Thi5, D‐Tic7, Oic8]BK) in a non‐competitive manner. In IMR‐90 cells, FR165649 had no agonistic effect on phosphatidyl inositol (PI) hydrolysis and caused parallel rightward shifts (approximately 200 fold shift at 10−7 M) of the concentration‐response curves to BK on PI hydrolysis. FR190997 induced concentration‐dependent PI hydrolysis in IMR‐90 cells with a pD2 of 8.4±0.1, and this effect was inhibited by Hoe 140. These results indicate that FR165649 and FR190997 are, respectively, a potent bradykinin B2 receptor antagonist and agonist, and that the agonistic activity depends on the small part of the nonpeptide ligand. FR165649 and FR190997 may be useful tools for studying the relationship between ligands and receptors.

Pharmacological characterization of a novel, orally active, nonpeptide bradykinin B2 receptor antagonist, FR167344

To investigate the pathophysiological role of bradykinin and to develop a drug for inflammatory diseases, we discovered an orally active, nonpeptide bradykinin B2 receptor antagonist, FR167344, N-[N-[3-[(3-bromo-2-methylimidazo[1,2-a]pyridin-8-yl)oxymethyl]-2, 4dichlorophenyl]-N-methylaminocarbonylmethyl]-4-(dimethyl aminocarbonyl) cinnamylamide hydrochloride. This compound competitively displaced [3H]bradykinin binding to bradykinin B2 receptors present in guinea-pig ileum membrane with an IC50 value of 6.6 X 10(-10) M. In isolated guinea-pig ileum preparations, it also antagonized bradykinin-induced contraction with a pA2 value of 9.3. In human lung fibroblast IMR-90 cells, FR167344 displaced [3H]bradykinin binding to human bradykinin B2 receptors with an IC50 value of 1.3 X 10(-8) M, but not [3H]des-Arg10-kallidin binding to human bradykinin B1 receptors. In vivo, oral administration of FR167344 inhibited bradykinin-induced bronchoconstriction in guinea pigs and the bradykinin-induced hypotensive response for 6 h in rats. These results show that FR167344 is a potent, selective, orally active and long acting bradykinin B2 receptor antagonist.

Identification of 4-quinolone derivatives as inhibitors of reactive oxygen species production from human umbilical vein endothelial cells

Oxidative stress is widely recognized as being associated with a number of disorders, including metabolic dysfunction and atherosclerosis. A series of substituted 4-quinolone derivatives were prepared and evaluated as inhibitors of reactive oxygen species (ROS) production from human umbilical vein endothelial cells (HUVECs). One compound in particular, 2-({[4-(3-hydroxy-3-methylbutoxy)pyridin-2-yl]oxy}methyl)-3-methylquinolin-4(1H)-one (25b), inhibited ROS production from HUVECs with an IC(50) of 140 nM. This compound also exhibited low CYP2D6 inhibitory activity, high aqueous solubility, and good in vitro metabolic stability. An in vivo pharmacokinetic study of this compound in SD rats revealed high oral bioavailability and a long plasma half-life.