Hayashi H, Miwa Y, Ichikawa S, Yoda N, Miki I, Ishii A, Kono M, Yasuzawa T, Suzuki F
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Company, Ltd., Shizuoka-ken, Japan.
J Med Chem. 1993 Mar 5;36(5):617-26. doi: 10.1021/jm00057a011.
A series of 4-hydroxy-3-quinolinecarboxylic acid derivatives (6) and 4-hydroxy-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid derivatives (7) were designed and synthesized as 5-HT3 receptor antagonists. Molecular modeling studies suggested that the 3-carbonyl moiety in 6 was almost coplanar to the plane of an aromatic ring, but in 7 there was a 30 degrees deviation. 4-Hydroxy substitution in quinoline derivatives enhanced affinity for the 5-HT3 receptors, and endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-4-hydroxy-3- quinolinecarboxamide (6f) exhibited the most potent activity in the Bezold-Jarisch (B-J) reflex test (ED50 = 0.1 micrograms/kg, iv) among quinoline derivatives 6. Although 4-hydroxy-2-oxo-1,2-dihydro-3-quinolinecarboxamide derivatives (7a) exhibited higher affinity (e.g., 7d: Ki = 0.48 nM) for the 5-HT3 receptors than ondansetron (Ki = 7.6 nM) or granisetron (Ki = 2.1 nM), these amides showed less potent activity in the B-J reflex test than the reference compounds. Interestingly, the ester derivatives 7c, 7f, and 7h eliminated affinity for the 5-HT3 receptors. These unusual structure-activity relationships and the deviation of the 3-carbonyl moiety from the plane of an aromatic ring suggest that the active conformation of 7a might be different from the proposed one for the preceding 5-HT3 antagonists. Thus, 6f was chosen for further studies. No receptor binding for a variety of ligands was significantly antagonized by 6f. Comparing the ratios of the ED50 value in the B-J reflex test (rat, iv) with the LD50 value in acute lethal toxicity (mouse, iv), 6f was proved to have a 600-fold wider margin of safety than ondansetron. Compound 6f dose-dependently attenuated both the incidence and frequency of emetic episodes induced by cisplatin in the dog (ED50 = 14 micrograms/kg, iv) more potently than ondansetron (ED50 = 210 micrograms/kg, iv). Compound 6f (KF-20170) is now under further investigation as a drug for treating gastrointestinal disorder.
设计并合成了一系列4-羟基-3-喹啉羧酸衍生物（6）和4-羟基-2-氧代-1,2-二氢-3-喹啉羧酸衍生物（7）作为5-羟色胺3（5-HT3）受体拮抗剂。分子模型研究表明，6中的3-羰基部分几乎与芳环平面共面，但在7中存在30度的偏差。喹啉衍生物中的4-羟基取代增强了对5-HT3受体的亲和力，并且内-N-（8-甲基-8-氮杂双环[3.2.1]辛-3-基）-4-羟基-3-喹啉甲酰胺（6f）在喹啉衍生物6的贝佐尔德-雅里什（B-J）反射试验（ED50 = 0.1微克/千克，静脉注射）中表现出最有效的活性。尽管4-羟基-2-氧代-1,2-二氢-3-喹啉甲酰胺衍生物（7a）对5-HT3受体的亲和力（例如，7d：Ki = 0.48纳摩尔）高于昂丹司琼（Ki = 7.6纳摩尔）或格拉司琼（Ki = 2.1纳摩尔），但这些酰胺在B-J反射试验中的活性比参考化合物低。有趣的是，酯衍生物7c、7f和7h消除了对5-HT3受体的亲和力。这些不寻常的构效关系以及3-羰基部分与芳环平面的偏差表明，7a的活性构象可能与先前5-HT3拮抗剂提出的构象不同。因此，选择6f进行进一步研究。6f对多种配体的受体结合没有明显拮抗作用。比较B-J反射试验（大鼠，静脉注射）中的ED50值与急性致死毒性（小鼠，静脉注射）中的LD50值的比率，证明6f的安全边际比昂丹司琼宽600倍。化合物6f剂量依赖性地减弱了顺铂诱导的犬呕吐发作的发生率和频率（ED50 = 14微克/千克，静脉注射），比昂丹司琼（ED50 = 210微克/千克，静脉注射）更有效。化合物6f（KF-20170）作为一种治疗胃肠疾病的药物目前正在进一步研究中。
