药物稳定性-王天才.ppt

⑴引入吸电子基团和空间位阻 Addition of a halogen to a phenolic compound reduces glucuronidation by electronwithdrawal and steric hindrance. Addition of a cyano group to the phenolic compound reduced glucuronidation while increasing activity. Journal of Medicinal Chemistry 45, 5755–5775 Isosteric replacement of the phenolic hydroxyl improved metabolic stability against glucuronidation. Journal of Medicinal Chemistry 48, 680–693 Phenols can be modified to form prodrugs. The free phenol is slowly released. Journal of Medicinal Chemistry 47, 2393–2404. 药物在血浆中可被水解酶降解 血浆中有大量的水解酶，如胆碱酯酶，醛缩酶，脂肪酶，脱氢肽(水解)酶，磷酸酶等 具有酯，酰胺，氨基甲酸酯，内酰胺，内酯，磺酰胺等官能团药物应测试血浆稳定性 水解药物可增加清除率 可通过增加位阻、吸电子基团等结构调整策略改善血浆稳定性 Chirality, 9, 661–666 Journal of Medicinal Chemistry, 47, 2393–2404 Antiinflammatory antedrugs 用酰胺代替酯 增加空间位阻 软药引入吸电子基团，降低血浆稳定性 消除易水解基团 Substitution of an amide for an ester greatly increased plasma stability and maintained activity Journal of Medicinal Chemistry, 43, 1234–1241 Increased steric hindrance of the lactam carbonyl increased plasma stability Journal of Medicinal Chemistry, 47,1375–1390 Introduce electron-withdrawing group to decrease plasma stability and increase clearance to avoid adverse effects using antedrug approach. Journal of Medicinal Chemistry, 45, 930–936. 化合物降解：PH, 水，辅料，离子，溶液成分(如dithiotheital (DTT))，温度，光照，氧，酶等 溶液稳定性可通过移除不稳定基团，增加位阻，引入吸电子基团等策略改善 移除或改变不稳定基团 引入吸电子基团 稳定基团的电子等排取代 增加空间位阻 Improvement of acidic stability of artemisinin analogs. Conditions were pH 2 at 37C. Journal of Medicinal Chemistry, 45, 4940–4944. Modification of the conjugated section and elimination of the ester greatly improved the stability and exposure of these lipoxin analogs Journal of Medicinal Chemistry, 47, 2157–2165 Addition of an electron-withdrawing cyano group reduced hydrolysis of the adjacent epoxide. Organic Letters, 4, 3815–3818 Dipeptidyl peptidase IV (DPP-IV) inhibitors. Chemical stability in pH 7.2 at 39.5°C. Introducing steric hindrance enhanced stability Journal of Medicinal Chemistry, 47, 2587–2598