Inamura N, Asano M, Kayakiri H, Hatori C, Oku T, Nakahara K
Drug Discovery Division, Fujisawa Pharmaceutical Co. Ltd., Osaka, Japan.
Can J Physiol Pharmacol. 1997 Jun;75(6):622-8.
Bradykinin (BK) is involved in different pathophysiological conditions, including allergic and (or) inflammatory reactions. Thus, BK antagonists are considered as a potential drug in allergic and (or) inflammatory diseases. Orally active BK antagonist would be desirable for this purpose. Here, we describe the pharmacological characterization of FR173657 ((E)-3-(6-acetamido-3-pyridyl)-N-[N-[2,4-dichloro-3-[(2-methyl-8- quinolinyl)oxymethyl]phenyl]-N-methylaminocarbonylmethyl]acr ylamide) obtained from our screening for nonpeptide, orally active B2 antagonists. (i) FR173657 antagonized [3H]BK binding with IC50 values of 4.6 x 10(-10) and 8.6 x 10(-9) M in membrane preparations of guinea pig ileum and lung, respectively. FR173657 inhibited [3H]BK binding to A431, W138, and IMR90 cell lines of human origin with IC50 values of 2.0 x 10(-9), 2.3 x 10(-9), and 1.7 x 10(-9) M, respectively. FR173657 did not affect [3H]des-Arg10-kallidin (B1 ligand) binding onto IMR90 cells. (ii) FR173657 inhibited guinea pig ileum contractions by BK (6 x 10(-8) M) with an IC50 value of 6.1 x 10(-9) M. Acetylcholine- and histamine-induced contraction of guinea pig ileum was unaffected by FR173657. (iii) Oral administration of FR173657 dose-dependently inhibited BK (5 micrograms/kg) and dextran sulfate (activator of kinin-kallikrein cascade) induced bronchoconstriction with ED50 values of 0.075 and 0.057 mg/kg, respectively. In conclusion, FR173657 is a selective potent, orally active B2 receptor antagonist that can be used to investigate the role of BK in allergic and inflammatory diseases.
缓激肽（BK）参与多种病理生理状况，包括过敏和（或）炎症反应。因此，BK拮抗剂被视为治疗过敏和（或）炎症性疾病的潜在药物。口服活性BK拮抗剂将是实现此目的的理想选择。在此，我们描述了从非肽类口服活性B2拮抗剂筛选中获得的FR173657（（E）-3-（6-乙酰氨基-3-吡啶基）-N-[N-[2,4-二氯-3-[(2-甲基-8-喹啉基)氧甲基]苯基]-N-甲基氨基羰基甲基]丙烯酰胺）的药理学特性。（i）FR173657在豚鼠回肠和肺的膜制剂中拮抗[3H]BK结合，IC50值分别为4.6×10^(-10)和8.6×10^(-9) M。FR173657抑制[3H]BK与人源A431、W138和IMR90细胞系的结合，IC50值分别为2.0×10^(-9)、2.3×10^(-9)和1.7×10^(-9) M。FR173657不影响[3H]去-Arg10-胰激肽（B1配体）与IMR90细胞的结合。（ii）FR173以6.1×10^(-9) M的IC50值抑制BK（6×10^(-8) M）引起的豚鼠回肠收缩。FR173657不影响乙酰胆碱和组胺诱导的豚鼠回肠收缩。（iii）口服FR173657剂量依赖性地抑制BK（5微克/千克）和硫酸葡聚糖（激肽-激肽释放酶级联反应激活剂）诱导的支气管收缩，ED50值分别为0.075和0.057毫克/千克。总之，FR173657是一种选择性强效口服活性B2受体拮抗剂，可用于研究BK在过敏和炎症性疾病中的作用。
