甲基在药物分子设计中的应用_连捷.pdfVIP

药学学报 Acta Pharmaceutica Sinica 2013, 48 (8): 1195?1208 · 1195 · 甲基在药物分子设计中的应用 连 捷 1, 2, 王 江 2, 孙海峰 2, 林岱宗 2, 柳 红 1, 2* (1. 中国药科大学药学院, 江苏 南京 210009; 2. 中国科学院上海药物研究所, 新药研究国家重点实验室, 上海 201203) 摘要: 甲基在药物分子的合理设计中起到重要作用, 如何巧妙地在分子中引入甲基已成为先导化合物结构 优化的重要改造策略之一。本文综述了在药物分子设计中一些合理引入甲基的应用实例。将甲基引入小分子中 通过影响脂溶性和水溶性改变药物的理化性质; 通过诱导效应、改变分子构象以及改变蛋白?配体相互作用影响 药物的药效性质; 通过邻位效应、弱代谢作用以及增加稳定性来影响药物的代谢性质; 同时, 甲基在 me-too 药物 研发以及老药新用研发策略中也起到重要作用。 关键词: 甲基; 药物设计; 结构优化; 空间电子效应; 脂溶性 中图分类号: R916 文献标识码: A 文章编号: 0513-4870 (2013) 08-1195-14 Application of methyl in drug design LIAN Jie1, 2, WANG Jiang2, SUN Hai-feng2, LIN Dai-zong2, LIU Hong1, 2* (1. School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China; 2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China) Abstract: The methyl group plays an important role in the rational drug design. Introducing methyl into small molecules has become an important strategy of lead compound optimization. The application of methyl in drug design is reviewed in this paper. Methyl can modulate the physicochemical, pharmacodynamic, and pharmacokinetic properties by ortho effect, inductive effect, and conformational effect. It also improves the metabolic stability as a soft metabolic point. In addition, introducing methyl into drug molecules can also be applied as a strategy in new uses of old drugs and generate me-too drugs. Key words: methyl; drug design; lead optimization; stereoelectronic effect; liposolubility