2-苯基嘧啶-5-甲酸类黄嘌呤氧化酶抑制剂的设计、合成及降尿酸活性研究  

Study on the design,synthesis and hypouricemic activity of 2-phenylpyrimidine-5-carboxylic acids xanthine oxidase inhibitors

作　　者：冯周平 毛青 王绍杰[2] FENG Zhouping;MAO Qing;WANG Shaojie(Hainan Huiyuantang Pharmaceutical Co.,Ltd.,Haikou 570311,China;Key Laboratory of Structure-Based Drugs Design&Discovery of Ministry of Education,(Shenyang Pharmaceutical University),Shenyang 110016,China)

机构地区：[1]海南回元堂药业有限公司,海南海口570311 [2]沈阳药科大学基于靶点的药物设计与研究教育部重点实验室,辽宁沈阳110016

出　　处：《中国药物化学杂志》2025年第1期1-9,共9页Chinese Journal of Medicinal Chemistry

摘　　要：目的设计合成2-苯基嘧啶-5-甲酸类化合物,评估其体外黄嘌呤氧化酶抑制活性及优选化合物的体内降尿酸活性。方法以4-异戊氧基-3-氰基苯甲脒盐酸盐为原料,经环合、水解反应得到化合物10~13,以4-苄氧基-3-氰基苯甲脒盐酸盐为原料,经环合、脱苄基、烃化和水解反应得到化合物11a~11m;采用紫外分光光度法对所合成的化合物进行体外黄嘌呤氧化酶抑制活性测试,采用氧嗪酸钾诱导的高尿酸血症大鼠模型对优选化合物11a进行体内降尿酸活性测试。结果设计并合成了17个未见文献报道的化合物,其结构均经^(1)H-NMR、^(13)C-NMR和HRMS谱确证。酶活性测试结果表明,除化合物12和13外,所有化合物均展现出一定的黄嘌呤氧化酶抑制活性,IC_(50)值为37~202 nmol·L^(-1),优选化合物11a的活性与先导化合物TMB-3相当,且体内降尿酸活性优于TMB-3。结论通过对TMB-3进行结构修饰,获得了与其体外活性相当但体内药效更优的化合物11a,同时拓展了2-苯基嘧啶-5-羧酸类黄嘌呤氧化酶抑制剂的构效关系,嘧啶4位为羟基时活性最优,但体内降尿酸活性较差,将羟基分别替换为氢或甲基时活性略有降低,替换为二氟甲基或三氟甲基时活性大幅降低。TMB-3 was a xanthine oxidase(XO)inhibitor identified in our previous study with an IC_(50)value of 25 nmol·L^(-1).However,it failed to demonstrate uric acid(UA)-lowing activity in vivo.To enhance the physicochemical properties and in vivo UA-lowing activity of TMB-3,seventeen 2-phenylpyrimidine-5-carboxylic acid derivatives were synthesized through cyclization,hydrolysis and other methods.Among these derivatives,compound 11a emerged as the most promising candidate,with an IC_(50)value of 37 nmol·L^(-1)against XO.Structure-activity relationship(SAR)analysis indicated that the XO inhibitory potency was optimal when a hydroxyl group was present at the 4-position of the pyrimidine ring,although its UA-lowing activity in vivo remained limited.Substituting the hydroxyl group with hydrogen or methyl resulted in a slight reduction in potency,whereas substitution with difluoromethyl or trifluoromethyl significantly impaired potency.Notably,in vivo studies revealed that compound 11a effectively reduced serum uric acid levels at an oral dose of 10 mg·kg^(-1).

关 键 词：2-苯基嘧啶-5-甲酸 黄嘌呤氧化酶抑制剂 降尿酸 合成 

分 类 号：R914[医药卫生—药物化学]