减肥药利莫那班的结构改造
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摘要
肥胖是全世界最大的成年人慢性疾病,其发病类和流行率在逐年上升,由它引起的高脂血症、动脉粥样硬化、冠心病、糖尿病等一系列代谢综合症直接威胁着患者的生命健康,因此寻找一种能针对各种潜在病因、改善多种心脏代谢性危险因素的减肥药显得十分迫切。利莫那班是首个开发用于肥胖治疗的大麻素受体拮抗剂,对大麻素1型受体有较好的选择性和亲和力,它除具有显著的降低体质量、减小腰围的作用外,还可降低血清甘油三酯、胆固醇、低密度脂蛋白,改善血脂和胰岛素抵抗以及多种代谢综合症。
鉴于利莫那班具有以上多种药理作用,我们根据现有文献报道的构效关系,设计合成了23个1,5-二芳基吡唑类利莫那班衍生物,其中17个是未见报道的新化合物,其结构经过核磁共振氢谱、碳谱以及质谱确认。
以利莫那班为阳性对照品,对其中合成的15个化合物进行了体外药理活性筛选,结果显示4个化合物体外活性较好,对大麻素1型受体抑制作用的浓度与利莫那班在同一个数量级范围内。
根据筛选结果,分析了这些化合物的构效关系,为下一步更好地研究提供依据。
Obesity is the most serious chronic disease of adults in the worldwide. The incidence and prevalence rates of obesity are rising year by year, many metabolic syndromes, such as heperlipidemia, atherosis, coronary disease, diabetes mellitus and so on results from obesity threaten patient's life and health directly. Therefore, To find an effective antiobesity drug which can aim at potential pathogenies and improve cardiovascular and metabolic risk factors are urgently needed. Rimonabant is the first selective cannabinoid receptor antagonist which was developed for obese therapy, having a good selectivity and affinity to cannabinoid type 1 receptor. Except markedly reduce body mass and waist circumference, it also can reduce triglycerides, cholesterol, low density lipoprotein, improve lipid, insulin resistance and many metabolic syndromes.
Since rimonabant has pleiotropic functions, we designed and synthesized 23 rimonabant analogues according to its structure-activity relationships, 17 compounds had never been reported, their structures were confirmed by nulclear magnetic resonance hydrogen and carbon spectrum and mass spectrum.
Take rimonabant as control experiment, 15 compounds' activity were tested in vitro, The results displayed that 4 compounds have a good activity in vitro, their inhibit concentrations to cannabinoid type 1 receptor at the same level with rimonabant.
Their structure-activity relationships were analyzed so as to providing bases for better reasearch it in the next step.
鉴于利莫那班具有以上多种药理作用,我们根据现有文献报道的构效关系,设计合成了23个1,5-二芳基吡唑类利莫那班衍生物,其中17个是未见报道的新化合物,其结构经过核磁共振氢谱、碳谱以及质谱确认。
以利莫那班为阳性对照品,对其中合成的15个化合物进行了体外药理活性筛选,结果显示4个化合物体外活性较好,对大麻素1型受体抑制作用的浓度与利莫那班在同一个数量级范围内。
根据筛选结果,分析了这些化合物的构效关系,为下一步更好地研究提供依据。
Obesity is the most serious chronic disease of adults in the worldwide. The incidence and prevalence rates of obesity are rising year by year, many metabolic syndromes, such as heperlipidemia, atherosis, coronary disease, diabetes mellitus and so on results from obesity threaten patient's life and health directly. Therefore, To find an effective antiobesity drug which can aim at potential pathogenies and improve cardiovascular and metabolic risk factors are urgently needed. Rimonabant is the first selective cannabinoid receptor antagonist which was developed for obese therapy, having a good selectivity and affinity to cannabinoid type 1 receptor. Except markedly reduce body mass and waist circumference, it also can reduce triglycerides, cholesterol, low density lipoprotein, improve lipid, insulin resistance and many metabolic syndromes.
Since rimonabant has pleiotropic functions, we designed and synthesized 23 rimonabant analogues according to its structure-activity relationships, 17 compounds had never been reported, their structures were confirmed by nulclear magnetic resonance hydrogen and carbon spectrum and mass spectrum.
Take rimonabant as control experiment, 15 compounds' activity were tested in vitro, The results displayed that 4 compounds have a good activity in vitro, their inhibit concentrations to cannabinoid type 1 receptor at the same level with rimonabant.
Their structure-activity relationships were analyzed so as to providing bases for better reasearch it in the next step.
引文
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