Casida John E
Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy, and Management, University of California , Berkeley, California 94720, United States.
Chem Res Toxicol. 2017 May 15;30(5):1117-1126. doi: 10.1021/acs.chemrestox.7b00030. Epub 2017 Apr 7.
What are the advantages of bioactivation in optimizing drugs and pesticides? Why are there so many prodrugs and propesticides? These questions are examined here by considering compounds selected on the basis of economic value or market success in 2015. The 100 major drugs and 90 major pesticides are divided into ones acting directly and those definitely or possibly requiring bioactivation. Established or candidate prodrugs accounted for 19% of the total drug sales, with corresponding values of 20, 37, and 17% for proinsecticides, proherbicides, and profungicides. The 19 prodrugs acting in humans generally had better pharmacodynamic/pharmacokinetic properties for target enzyme, receptor, tissue, or organ specificity due to their physical properties (lipophilicity and stabilization). Bioactivation usually involved hydrolases or cytochrome P450 oxidation or reduction. Prodrugs considered are neuroactive aripiprazole, eletriptan, desvenlafaxin, lisdexamfetamine, quetiapine, and fesoterodine; cholesterol-lowering atorvastatin, ezetimibe, and fenofibrate; various prodrugs activated by esterases or sulfatases, ciclesonide, oseltamivir, dabigatran; omega-3 fatty acid ethyl esters and esterone sulfate; and five others with various targets (sofosbuvir, fingolimod, clopidogrel, dapsone, and sildenafil). The proinsecticides are the neuroactive chlorpyrifos, thiamethoxam, and indoxacarb, two spiro enol ester inhibitors of acetyl CoA carboxylase (ACCase), and the bacterial protein delta-endotoxin. The proherbicides considered are five ACCase inhibitors including pinoxaden and clethodim, three protox inhibitors (saflufenacil, flumioxazin, and canfentrazone-ethyl), and three with various targets (fluroxypyr, isoxaflutole, and clomazone). The profungicides are prothioconazole, mancozeb, thiophanate-methyl, dazomet, and fosetyl-aluminum. The prodrug and propesticide concept is broadly applicable and has created some of the most selective pharmaceutical and pest control agents, illustrated here by major compounds that partially overcome pharmacokinetic limitations of potency and selectivity in the corresponding direct-acting compounds. The challenges of molecular design extend beyond the target site fit to the bioactivatable precursor and the fascinating chemistry and biology matched against the complexity of life processes.
生物活化在优化药物和农药方面有哪些优势？为什么会有如此多的前体药物和前体农药？本文通过研究2015年基于经济价值或市场成功而选择的化合物来探讨这些问题。100种主要药物和90种主要农药被分为直接起作用的以及肯定或可能需要生物活化的两类。已上市或候选的前体药物占药物总销售额的19%，前体杀虫剂、前体除草剂和前体杀真菌剂的相应比例分别为20%、37%和17%。19种作用于人体的前体药物由于其物理性质（亲脂性和稳定性），对于靶酶、受体、组织或器官特异性通常具有更好的药效学/药代动力学性质。生物活化通常涉及水解酶或细胞色素P450氧化或还原。所考虑的前体药物有神经活性药物阿立哌唑、依来曲普坦、去甲文拉法辛、赖氨酸安非他命、喹硫平和非索非那定；降胆固醇药物阿托伐他汀、依折麦布和非诺贝特；由酯酶或硫酸酯酶激活的各种前体药物，环索奈德、奥司他韦、达比加群；ω-3脂肪酸乙酯和硫酸雌酮；以及其他五种具有不同靶点的药物（索磷布韦、芬戈莫德、氯吡格雷、氨苯砜和西地那非）。前体杀虫剂有神经活性药物毒死蜱、噻虫嗪和茚虫威，两种乙酰辅酶A羧化酶（ACCase）的螺环烯醇酯抑制剂，以及细菌蛋白δ-内毒素。所考虑的前体除草剂有五种ACCase抑制剂，包括丙酯草醚和炔草酯，三种原卟啉原氧化酶（protox）抑制剂（乙羧氟草醚、氟嘧磺隆和乙氧氟草醚），以及三种具有不同靶点的药物（氟草烟、异恶唑草酮和异噁草酮）。前体杀真菌剂有丙硫菌唑、代森锰锌、甲基硫菌灵、棉隆和乙膦铝。前体药物和前体农药的概念具有广泛的适用性，并且产生了一些最具选择性的药物和害虫防治剂，本文通过主要化合物举例说明，这些化合物部分克服了相应直接作用化合物在效力和选择性方面的药代动力学限制。分子设计的挑战不仅在于靶位点与可生物活化前体的匹配，还在于与生命过程复杂性相匹配的迷人化学和生物学。
