Evaluation of Deuterium-Labeled JNJ38877605: Pharmacokinetic, Metabolic, and in Vivo Antitumor Profiles
文献类型：期刊论文
| 作者 | Zhan, Zhengsheng2; Peng, Xia1; Sun, Yiming1; Ai, Jing2 ; Duan, Wenhu2
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| 刊名 | CHEMICAL RESEARCH IN TOXICOLOGY
 |
| 出版日期 | 2018-11 |
| 卷号 | 31期号:11页码:1213-1218 |
| ISSN号 | 0893-228X |
| DOI | 10.1021/acs.chemrestox.8b00191 |
| 文献子类 | Article |
| 英文摘要 | c-Met inhibitor JNJ38877605 has proven curative as an antitumor agent, while its clinical study was terminated due to renal toxicity. It was reported that the renal toxicity was caused by the poor solubility of its aldehyde oxidase (AO) metabolites. Therefore, blocking AO oxidation of JNJ38877605 might diminish the toxic metabolites and overcome the renal toxicity. Compound 3, the AO metabolic site deuterated JNJ38877605, was then synthesized as the target molecule. In vitro monkey liver S9 fraction incubation of 3 manifested that the renal toxic metabolite M2-2 was significantly reduced, which connoted that this deuteration has partly blocked AO oxidation. After po. nasal gavage to cynomolgus monkeys, compound 3 revealed decreased AO metabolites M2-2 and M3-2 in the plasma as well as 1.88-fold AUC and 1.56-fold C-max compared with JNJ38877605, indicating that deuterium replacement significantly blocked AO metabolism in vivo. Besides, metabolic profiles of 3 were investigated by analysis of the plasma and the urine of the po. administrated cynomolgus monkeys. Moreover, after oral administration to the EBC-1 tumor-bearing nude mice, compound 3 exhibited a better antitumor efficacy than JNJ38877605. In conclusion, deuteration on the AO metabolic site of JNJ38877605 improved its AO metabolism, oral exposure, as well as in vivo antitumor efficacy. |
| WOS关键词 | C-MET INHIBITOR ; ALDEHYDE OXIDASE ; RENAL TOXICITY ; DISCOVERY ; GROWTH ; POTENT ; VOLITINIB ; RECEPTOR |
| 资助项目 | Shanghai Sailing Program[17YF1423300] ; Youth Innovation Promotion Association of CAS[2018324] ; Major Projects in National Science and Technology of China[2018ZX09711002-011-016] ; Major Projects in National Science and Technology of China[2018ZX09711002-004-013] ; National Natural Science Foundation of China[81573271] ; National Natural Science Foundation of China[21702220] |
| WOS研究方向 | Pharmacology & Pharmacy ; Chemistry ; Toxicology |
| 语种 | 英语 |
| WOS记录号 | WOS:000451245200015 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279506]  |
| 专题 | 药理学第一研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 药物化学研究室 |
| 通讯作者 | Ai, Jing; Duan, Wenhu |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Medica, State Key Lab Drug Res, Div Antitumor Pharmacol, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Medica, Dept Med Chem, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Zhan, Zhengsheng,Peng, Xia,Sun, Yiming,et al. Evaluation of Deuterium-Labeled JNJ38877605: Pharmacokinetic, Metabolic, and in Vivo Antitumor Profiles[J]. CHEMICAL RESEARCH IN TOXICOLOGY,2018,31(11):1213-1218. |
| APA | Zhan, Zhengsheng,Peng, Xia,Sun, Yiming,Ai, Jing,&Duan, Wenhu.(2018).Evaluation of Deuterium-Labeled JNJ38877605: Pharmacokinetic, Metabolic, and in Vivo Antitumor Profiles.CHEMICAL RESEARCH IN TOXICOLOGY,31(11),1213-1218. |
| MLA | Zhan, Zhengsheng,et al."Evaluation of Deuterium-Labeled JNJ38877605: Pharmacokinetic, Metabolic, and in Vivo Antitumor Profiles".CHEMICAL RESEARCH IN TOXICOLOGY 31.11(2018):1213-1218. |
入库方式： OAI收割
来源：上海药物研究所
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