郭宗儒:药物创新与反向思维 33l CH 2(MWl80) 23(MW129) 24(MWl59) 25(MWI95) 26(MWI90 血药物丁苯酞(26,N- butylphthalide)等等,对于超小 blocker J Physiol, 2010, 588: 3157-3167 分子药物确实不容忽视。这些药物结构简单,物化性61 Kang j, Chen x, Wang h, et al. Discovery of a small molecule 质好,对活性和选择性一旦达标,成药性无多障碍, activator of the human ether-a-go-go-related gene (HERG) 而且对生物药剂学的容纳性也很强。 cardiac K channel []. Mol Pharmacol, 2005, 67: 827-836. 结语 [7 Zhou J, Augelli-Szafran CE, Bradley JA, et al. Novel potent 新药创制是人类最复杂的智力活动之一,周期 human ether-a-go-go-related gene(hERG) potassium channel 长,风险大。每个药物的创制都是个性化的分子操作, enhancers and their in vitro antiarrhythmic activity [] Mol 各自都有难以复制的研发轨迹。将活性化合物转化成 Pharmacol,2005,68:876-884 药物的过程,几乎是在没有规律性、没有周期性变化 Gerlach Ac, Stoehr SJ, Castle NA. Pharmacological removal 的混沌系统中进行的。尽管如此,由于研发者在研究 of human ether-a-go-go-related gene potassium channel 目标、策略、路径、技术和方法具有趋同性,突破性 inactivation by 3-nitro-N-(4-phenoxyphenyl) benzamide (ICA- 和颠覆性的创新较少(典型的例子是最近相继上市 105574). Mol pharmacol,2010,77:58-68 的数个“列净”药物,都是以抑制SGLT2为靶标 [9 Itoh Z, Omura S. Motilide, a new family of macrolide compounds mimicing motilin []. Dig Dis Sci, 1987, 32 以根皮苷为先导物研发的,即使是保密和独立进行, 上市的药物结构和药理活性很相近)。在这样的大环 [10 Omura S, Tsuzuki K, Sunazuka T, et al. Macrolides with 境下,基于靶标和化合物的杂泛性( promiscuity,通 gastrointestinal motor stimulating activity [] J Med Chem, 过反向思维而标新立异,或许可辟出新的路径。 [11 Hadvary P, Sidler W, Meister W, et al. The lipase inhibitor References tetrahydrolipstatin binds covalently to the putative site serine [1] Munos B. A forensic analysis of drug targets from 2000 of pancreatic lipase U. J Biol Chem, 1991, 266: 2021-2027 nrough 2012 P ]. Clin Pharmacol Ther, 2013, 94: 407-411 [12 Pereillo JM, Maftouh M, Andrieu A, et al. Structure and [2] Breslin HJ, Diamond CJ, Kavash RW, et al. Identification of stereochemistry of the active metabolite of clopidogrel a dual d OR antagonist/u OR agonist as a potential therapeutic Drug Metab Dispos, 2002, 30: 1288-1295. for diarrhea-predominant Irritable Bowel Syndrome(IBS-d [13] Cattaneo M. ADP receptors: inhibitory strategies for antiplatelet U]. Bioorg Med Chem Lett, 2012, 22: 4869-4572 therapy []. Drug News Perspect, 2006, 19: 253-259 3 Guo ZR. Iluxadoline: developed based on peptide ligands j [14] Wissner A, Overbeek E, Reich M, et al thesis and structure. Acta Pharm Sin(药学学报),2015,50:1068-1072. activity relationship of 6,7-disubstituted 4-anilinoquinoline- [4] Chen X, Zhao C, Liu L, et al. Terazosin activates PgkI and 3-carbonitriles. The design of an orally active, irreversible HSP90 to promote stress resistance J]. Nat Chem Biol, 2015 ahibitor of the tyrosine kinase activity of the epidermal 5 Perry M, Sanguinetti M, Micheson J. Revealing the structural growth factor receptor-2(HER-2)[]. J Med Chem, 200 bases of action of hERG potassium channel activator and 46:49-63.郭宗儒: 药物创新与反向思维 · 331 · 血药物丁苯酞 (26, N-butylphthalide) 等等, 对于超小 分子药物确实不容忽视。这些药物结构简单, 物化性 质好, 对活性和选择性一旦达标, 成药性无多障碍, 而且对生物药剂学的容纳性也很强。 7 结语 新药创制是人类最复杂的智力活动之一, 周期 长, 风险大。每个药物的创制都是个性化的分子操作, 各自都有难以复制的研发轨迹。将活性化合物转化成 药物的过程, 几乎是在没有规律性、没有周期性变化 的混沌系统中进行的。尽管如此, 由于研发者在研究 目标、策略、路径、技术和方法具有趋同性, 突破性 和颠覆性的创新较少 (典型的例子是最近相继上市 的数个“列净”药物, 都是以抑制 SGLT2 为靶标、 以根皮苷为先导物研发的, 即使是保密和独立进行, 上市的药物结构和药理活性很相近)。在这样的大环 境下, 基于靶标和化合物的杂泛性 (promiscuity), 通 过反向思维而标新立异, 或许可辟出新的路径。 References [1] Munos B. A forensic analysis of drug targets from 2000 through 2012 [J]. Clin Pharmacol Ther, 2013, 94: 407 −411. [2] Breslin HJ, Diamond CJ, Kavash RW, et al. Identification of a dual δ OR antagonist/μ OR agonist as a potential therapeutic for diarrhea-predominant Irritable Bowel Syndrome (IBS-d) [J]. Bioorg Med Chem Lett, 2012, 22: 4869 −4572. [3] Guo ZR. Iluxadoline: developed based on peptide ligands [J]. Acta Pharm Sin (药学学报), 2015, 50: 1068−1072. [4] Chen X, Zhao C, Liu L, et al. Terazosin activates Pgk1 and HSP90 to promote stress resistance [J]. Nat Chem Biol, 2015, 11: 19−25. [5] Perry M, Sanguinetti M, Micheson J. Revealing the structural bases of action of hERG potassium channel activator and blocker [J]. J Physiol, 2010, 588: 3157 −3167. [6] Kang J, Chen X, Wang H, et al. Discovery of a small molecule activator of the human ether-a-go-go-related gene (HERG) cardiac K+ channel [J]. Mol Pharmacol, 2005, 67: 827 −836. [7] Zhou J, Augelli-Szafran CE, Bradley JA, et al. Novel potent human ether-a-go-go-related gene (hERG) potassium channel enhancers and their in vitro antiarrhythmic activity [J]. Mol Pharmacol, 2005, 68: 876−884. [8] Gerlach AC, Stoehr SJ, Castle NA. Pharmacological removal of human ether-a-go-go-related gene potassium channel inactivation by 3-nitro-N-(4-phenoxyphenyl) benzamide (ICA- 105574) [J]. Mol Pharmacol, 2010, 77: 58 −68. [9] Itoh Z, Omura S. Motilide, a new family of macrolide compounds mimicing motilin [J]. Dig Dis Sci, 1987, 32: 915. [10] Omura S, Tsuzuki K, Sunazuka T, et al. Macrolides with gastrointestinal motor stimulating activity [J]. J Med Chem, 1987, 30: 1941−1943. [11] Hadvary P, Sidler W, Meister W, et al. The lipase inhibitor tetrahydrolipstatin binds covalently to the putative site serine of pancreatic lipase [J]. J Biol Chem, 1991, 266: 2021 −2027. [12] Pereillo JM, Maftouh M, Andrieu A, et al. Structure and stereochemistry of the active metabolite of clopidogrel [J]. Drug Metab Dispos, 2002, 30: 1288 −1295. [13] Cattaneo M. ADP receptors: inhibitory strategies for antiplatelet therapy [J]. Drug News Perspect, 2006, 19: 253 −259. [14] Wissner A, Overbeek E, Reich M, et al. Synthesis and structure￾activity relationship of 6,7-disubstituted 4-anilinoquinoline- 3-carbonitriles. The design of an orally active, irreversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor-2 (HER-2) [J]. J Med Chem, 2003, 46: 49−63