Hayashi H, Ikeda J, Kubo K, Moriyama T, Karasawa A, Suzuki F
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Chem Pharm Bull (Tokyo). 1993 Jun;41(6):1100-10. doi: 10.1248/cpb.41.1100.
A series of 5-(4-aryl- or 4-arylcarbonylpiperazin-1-yl)-5-deoxy-1,4: 3,6-dianhydro-L-iditol 2-nitrates was prepared in order to obtain orally active, nitrate-type vasodilators with reduced side effects. Our drug design was based on a small reduction in the lipophilicity compared to that of 5-deoxy-5-[4-(3-phenylthiopropyl)piperazin-1-yl]-1,4: 3,6-dianhydro-L-iditol 2-nitrate (1, KF14124). Compounds 4h (aryl = benzimidazol-2-yl), 4i (arylcarbonyl = nicotinoyl), and 4w (arylcarbonyl = 3-furoyl) showed potent anti-ischemic activity in a lysine-vasopressin-induced angina pectoris model (rats), and their structure-activity relationships are discussed. Compound 4i exhibited potent vasodilation of the coronary artery in anesthetized dogs and also exhibited potent preload reduction in a heart failure model (dogs) as compared with isosorbide dinitrate (2), nicorandil (3), and KF14124 (1). Furthermore, 4i showed much weaker acute lethal toxicity and less central nervous system depression than 1 in mice. Thus, 4i (KW-3196) is under development as a vasodilator and a drug for treating angina pectoris.
为了获得具有口服活性且副作用减少的硝酸盐类血管舒张剂，制备了一系列5-(4-芳基-或4-芳基羰基哌嗪-1-基)-5-脱氧-1,4:3,6-二脱水-L-艾杜醇2-硝酸盐。我们的药物设计基于与5-脱氧-5-[4-(3-苯基硫丙基)哌嗪-1-基]-1,4:3,6-二脱水-L-艾杜醇2-硝酸盐(1，KF14124)相比亲脂性略有降低。化合物4h(芳基=苯并咪唑-2-基)、4i(芳基羰基=烟酰基)和4w(芳基羰基=3-呋喃甲酰基)在赖氨酸加压素诱导的心绞痛模型(大鼠)中显示出强效抗缺血活性，并对它们的构效关系进行了讨论。与硝酸异山梨酯(2)、尼可地尔(3)和KF14124(1)相比，化合物4i在麻醉犬中表现出强效冠状动脉舒张作用，并且在心力衰竭模型(犬)中也表现出强效前负荷降低作用。此外，在小鼠中，4i的急性致死毒性比1弱得多，对中枢神经系统的抑制作用也更小。因此，4i(KW-3196)正在作为一种血管舒张剂和治疗心绞痛的药物进行研发。
