药学学报, 2014, 49(1): 1-15
刘海龙, 王江, 林岱宗, 柳红. 先导化合物结构优化策略(二)——结构修饰降低潜在毒性[J]. 药学学报, 2014, 49(1): 1-15.
LIU Hai-long, WANG Jiang, LIN Dai-zong, LIU Hong. Lead compound optimization strategy (2)——structure optimization strategy for reducing toxicity risks in drug design[J]. Acta Pharmaceutica Sinica, 2014, 49(1): 1-15.

刘海龙1,2, 王江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受体结构与功能重点实验室, 上海 201203
关键词:    药物毒性      警惕结构      药物特质性毒性反应      CYP450      优化策略     
Lead compound optimization strategy (2)——structure optimization strategy for reducing toxicity risks in drug design
LIU Hai-long1,2, WANG Jiang2, LIN Dai-zong2, LIU Hong1,2
1. School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China;
2. Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Idiosyncratic adverse drug reactions (IDR) induce severe medical complications or even death in patients. Alert structure in drugs can be metabolized as reactive metabolite (RM) in the bodies, which is one of the major factors to induce IDR. Structure modification and avoidance of alert structure in the drug candidates is an efficient method for reducing toxicity risks in drug design. This review briefly summarized the recent development of the methodologies for structure optimization strategy to reduce the toxicity risks of drug candidates. These methods include blocking metabolic site, altering metabolic pathway, reducing activity, bioisosterism, and prodrug.
Key words:    drug toxicity    alert structure    idiosyncratic adverse drug reaction    CYP450    optimization strategy   
收稿日期: 2013-07-17
基金项目: 国家杰出青年科学基金资助项目(81025017).
通讯作者: 柳红
Email: hliu@mail.shcnc.ac.cn
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林岱宗  在本刊中的所有文章
柳红  在本刊中的所有文章

[1] Lasser KE, Allen PD, Woolhandler SJ, et al. Timing of new black box warnings and withdrawals for prescription medications[J]. J Am Med Ass, 2002, 287: 2215-2220.
[2] Nassar AEF, Kamel AM, Clarimont C. Improving the decision-making process in structural modification of drug candidates[J]. Drug Discov Today, 2004, 9: 1055-1064.
[3] Fieser LF. Carcinogenic activity, structure, and chemical reactivity of polynuclear aromatic hydrocarbons[J]. Am J Cancer, 1938, 34: 37-124.
[4] Kalgutkar AS, Soglia JR. Minimizing the potential for metabolic activation in drug discovery[J]. Expert Opin Drug Metab Toxicol, 2005, 1: 91-142.
[5] Matzinger P. The danger model: a renewed sense of self[J]. Science, 2002, 296: 301-305.
[6] Hess DA, Sisson ME, Suria H, et al. Cytotoxicity of sulfonamide reactive metabolites: apoptosis and selective toxicity of CD8(+) cells by the hydroxylamine of sulfamethoxazole[J]. FASEB J, 1999, 13: 1688-1698.
[7] Xu JJ, Diaz D, O'Brien PJ. Applications of cytotoxicity assays and pre-lethal mechanistic assays for assessment of human hepatotoxicity potential[J]. Chem Biol Interact, 2004, 150: 115-128.
[8] Pumford NR, Halmes NC. Protein targets of xenobiotic reactive intermediates[J]. Annu Rev Pharmacol Toxicol, 1997, 37: 91-117.
[9] Yuan L, Kaplowitz N. Glutathione in liver diseases and hepatotoxicity[J]. Mol Aspects Med, 2009, 30: 29-41.
[10] Jollow DJ, Mitchell JR, Potter WZ, et al. Acetaminophen-induced hepatic necrosis. 2. Role of covalent binding in vivo[J]. J Pharmacol Exp Ther, 1973, 187: 195-202.
[11] Jollow DJ, Thorgeirsson SS, Potter WZ, et al. Acetaminophen-induced hepatic necrosis. 6. Metabolic disposition of toxic and nontoxic doses of acetaminophen[J]. Pharmacology, 1974, 12: 251-271.
[12] Prescott LF. 3rd Lilly prize lecture. University of London, January, 1979. The nephrotoxicity and hepatotoxicity of antipyretic analgesics[J]. Br J Clin Pharmacol, 1979, 7: 453-462.
[13] Wirth PJ, Dybing E, Vonbahr C, et al. Mechanism of N-hydroxyacetylarylamine mutagenicity in the Salmonella test system-metabolic-activation of N-hydroxyphenacetin by liver and kidney fractions from rat, mouse, hamster, and man[J]. Curr Mol Pharmacol, 1980, 18: 117-127.
[14] Keesey J, Bein M, Mink J, et al. Chest radiography, tomography, and computed tomography for detection of thymoma in myasthenia-gravis[J]. Neurology, 1978, 28: 371.
[15] Neftel KA, Woodtly W, Schmid M, et al. Amodiaquine induced agranulocytosis and liver-damage[J]. Br Med J, 1986, 292: 721-723.
[16] O'Neill PM, Shone AE, Stanford D, et al. Synthesis, antimalarial activity, and preclinical pharmacology of a novel series of 4'-fluoro and 4'-chloro analogues of amodiaquine. Identification of a suitable "back-up" compound for N-tert-butyl isoquine[J]. J Med Chem, 2009, 52: 1828-1844.
[17] Kassahun K, Pearson PG, Tang W, et al. Studies on the metabolism of troglitazone to reactive intermediates in vitro and in vivo. Evidence for novel biotransformation pathways involving quinone methide formation and thiazolidinedione ring scission[J]. Chem Res Toxicol, 2001, 14: 62-70.
[18] Kalgutkar AS, Vaz AND, Lame ME, et al. Bioactivation of the nontricyclic antidepressant nefazodone to a reactive quinone-imine species in human liver microsomes and recombinant cytochrome P4503A4[J]. Drug Metab Dispos, 2005, 33: 243-253.
[19] Bauman JN, Frederick KS, Sawant A, et al. Comparison of the bioactivation potential of the antidepressant and hepatotoxin nefazodone with aripiprazole, a structural analog and marketed drug[J]. Drug Metab Dispos, 2008, 36: 1016-1029.
[20] Damsten MC, de Vlieger JSB, Niessen WMA, et al. Trimethoprim: novel reactive intermediates and bioactivation pathways by cytochrome P450s[J]. Chem Res Toxicol, 2008, 21: 2181-2187.
[21] Li XH, Kamenecka TM, Cameron MD. Bioactivation of the epidermal growth factor receptor inhibitor gefitinib: implications for pulmonary and hepatic toxicities[J]. Chem Res Toxicol, 2009, 22: 1736-1742.
[22] Wang J, Davis M, Li F, et al. A novel approach for predicting acyl glucuronide reactivity via Schiff base formation: development of rapidly formed peptide adducts for LC/MS/MS measurements[J]. Chem Res Toxicol, 2004, 17: 1206-1216.
[23] Walker GS, Atherton J, Bauman J, et al. Determination of degradation pathways and kinetics of acyl glucuronides by NMR spectroscopy[J]. Chem Res Toxicol, 2007, 20: 876-886.
[24] Baba A, Yoshioka T. Structure-activity relationships for the degradation reaction of 1-beta-O-acyl glucuronides. Part 3: electronic and steric descriptors predicting the reactivity of aralkyl carboxylic acid 1-beta-O-acyl glucuronides[J]. Chem Res Toxicol, 2009, 22: 1998-2008.
[25] Tadao Y, Akiko B. Structure-activity relationships for the degradation reaction of 1-β-O-acyl glucuronides. Part 2: electronic and steric descriptors predicting the reactivity of 1-β-O-acyl glucuronides derived from benzoic acids[J]. Chem Res Toxicol, 2009, 22: 1559-1569.
[26] Lloyd S, Hayden MJ, Sakai Y, et al. Differential in vitro hepatotoxicity of troglitazone and rosiglitazone among cryopreserved human hepatocytes from 37 donors[J]. Chem Biol Interact, 2002, 142: 57-71.
[27] Bonierbale E, Valadon P, Pons C, et al. Opposite behaviors of reactive metabolites of tienilic acid and its isomer toward liver proteins: use of specific anti-tienilic acid-protein adduct antibodies and the possible relationship with different hepatotoxic effects of the two compounds[J]. Chem Res Toxicol, 1999, 12: 286-296.
[28] Dansette PM, Bertho G, Mansuy D. First evidence that cytochrome P450 may catalyze both S-oxidation and epoxidation of thiophene derivatives[J]. Biochem Biophys Res Commun, 2005, 338: 450-455.
[29] O'Donnell JP, Dalvie DK, Kalgutkar AS, et al. Mechanism-based inactivation of human recombinant P450 2C9 by the nonsteroidal anti-inflammatory drug suprofen[J]. Drug Metab Dispos, 2003, 31: 1369-1377.
[30] Stepan AF, Walker DP, Bauman J, et al. Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States[J]. Chem Res Toxicol, 2011, 24: 1345-1410.
[31] Obach RS, Kalgutkar AS, Ryder TF, et al. In vitro metabolism and covalent binding of enol-carboxamide derivatives and anti-inflammatory agents sudoxicam and meloxicam: insights into the hepatotoxicity of sudoxicam[J]. Chem Res Toxicol, 2008, 21: 1890-1899.
[32] Shan J, Zhang B, Zhu Y, et al. Overcoming clopidogrel resistance: discovery of vicagrel as a highly potent and orally bioavailable antiplatelet agent[J]. J Med Chem, 2012, 55: 3342-3352.
[33] Fox KAA. Acute coronary syndromes in 2010: progress from trials to practice[J]. Nat Rev Cardiol, 2011, 8: 68-70.
[34] Liu ZC, Uetrecht JP. Clozapine is oxidized by activated human neutrophils to a reactive nitrenium ion that irreversibly binds to the cells[J]. J Pharmacol Exp Ther, 1995, 275: 1476-1483.
[35] Uetrecht J, Zahid N, Tehim A, et al. Structural features associated with reactive metabolite formation in clozapine analogues[J]. Chem Biol Interact, 1997, 104: 117-129.
[36] Cravedi JP, Perdudurand E, Baradat M, et al. Chloramphenicol oxamylethanolamine as an end-product of chloramphenicol metabolism in rat and humans: evidence for the formation of a phospholipid adduct[J]. Chem Res Toxicol, 1995, 8: 642-648.
[37] Notley LM, de Wolf CJF, Wunsch RM, et al. Bioactivation of tamoxifen by recombinant human cytochrome P450 enzymes[J]. Chem Res Toxicol, 2002, 15: 614-622.
[38] Adusumalli VE, Choi YM, Romanyshyn LA, et al. Isolation and identification of 3-carbamoyloxy-2-phenylpropionic acid as a major human urinary metabolite of felbamate[J]. Drug Metab Dispos, 1993, 21: 710-716.
[39] Roecklein BA, Sacks HJ, Mortko H, et al. Fluorofelbamate[J]. Neurotherapeutics, 2007, 4: 97-101.
[40] Smith KS, Smith PL, Heady TN, et al. In vitro metabolism of tolcapone to reactive intermediates: relevance to tolcapone liver toxicity[J]. Chem Res Toxicol, 2003, 16: 123-128.
[41] Wikberg T, Vuorela A, Ottoila P, et al. Identification of major metabolites of the catechol-O-methyltransferase inhibitor entacapone in rats and humans[J]. Drug Metab Dispos, 1993, 21: 81-92.
[42] Boelsterli UA, Ho HK, Zhou SF, et al. Bioactivation and hepatotoxicity of nitroaromatic drugs[J]. Curr Drug Metab, 2006, 7: 715-727.
[43] Yang M, Chordia MD, Li FP, et al. Neutrophil-and myeloperoxidase-mediated metabolism of reduced nimesulide: evidence for bioactivation[J]. Chem Res Toxicol, 2010, 23: 1691-1700.
[44] Jean-François R, Deniz A, Nancy G, et al. Analogues of nimesulide: design, synthesis, and in vitro and in vivo pharmacological evaluation as promising cyclooxyge nase 1 and 2 inhibitors[J]. J Med Chem, 2009, 52: 5864-5871.
[45] Uetrecht J. Prediction of a new drug's potential to cause idiosyncratic reactions[J]. Curr Opin Drug Discov Dev, 2001, 4: 55-59.
[46] Walgren JL, Mitchell MD, Thompson DC. Role of metabolism in drug-induced idiosyncratic hepatotoxicity[J]. Crit Rev Toxicol, 2005, 35: 325-361.
[47] Fromenty B, Pessayre D. Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity[J]. Aliment Pharmacol Ther, 1995, 67: 101-154.