Synthesis and in Vitro Characterization of Drug Conjugates of l-carnitine as Potential Prodrugs That Target Human Octn2
Synthesis and in Vitro Characterization of Drug Conjugates of l-carnitine as Potential Prodrugs That Target Human Octn2
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DOI：
10.1002/jps.22557
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发表时间：
2011-09-01
影响因子：
3.8
通讯作者：
Polli, James E.
中科院分区：
文献类型：
--
作者：
Diao, Lei;Polli, James E.
目的是评估具有L-肉毒碱的药物缀合物作为靶向有机阳离子/肉毒碱转运体（OCTN 2）的前药的潜力。评价了22种L-肉毒碱类似物对人有机阳离子/肉毒碱转运蛋白（hOCTN 2）的抑制作用;在L-肉毒碱上的三个官能团中，发现3 '-羟基是唯一不促进L-肉毒碱与hOCTN 2相互作用的官能团（即，3 '-羟基、胺和羧酸酯）。因此，选择L-肉毒碱上的3 '-羟基作为缀合位点。三种药物-L-肉毒碱缀合物（即，丙戊酸-L-肉碱、萘普生-L-肉碱和酮洛芬-L-肉碱）与在酮洛芬和L-肉碱之间引入连接基团（乙醇酸或甘氨酸）的两种酮洛芬类似物一起合成（即，酮洛芬-乙醇酸-L-肉毒碱和酮洛芬-甘氨酸-L-肉毒碱）。评价这些潜在前药的体外抑制、转运和代谢特性。所有三种药物-l-肉毒碱缀合物和酮洛芬-甘氨酸-l-肉毒碱都是0 CTN 2抑制剂以及底物。对于丙戊酸-L-肉毒碱，Ki = 155 +/- 19 μ M，K-m = 132 +/- 23 μ M，标准化J（max）= 0.467 +/- 0.028;对于萘普生-L-肉毒碱，Ki = 5.97 ± 0.81 μ M，K-m = 257 ± 57 μ M，标准化J（max）= 0.141 ± 0.012;对于酮洛芬-L-肉毒碱，Ki = 82.2 ± 5.3 μ M，K-m = 77.0 ± 4.0 μ M，标准化J（max）= 0.412 ± 0.015;对于酮洛芬-甘氨酸-L-肉毒碱，Ki = 14.4 +/- 1.4 μ M，K-m = 58.5 +/- 8.7 μ M，标准化J（max）= 0.0789 +/- 0.0037。酮洛芬-乙醇酸-l-肉碱在代谢缓冲液和化学缓冲液中不稳定。相反，萘普生-L-肉毒碱、酮洛芬-L-肉毒碱和酮洛芬-甘氨酸-L-肉毒碱在化学和代谢缓冲液中稳定。结果证明了药物-1-肉毒碱缀合物用作靶向0 CTN 2的前药的潜力。(C)2011 Wiley-Liss，Inc.和American Pharmacologist Association J Pharm Sci 100：3802-3816，2011
The objective was to evaluate the potential of drug conjugates with l-carnitine as prodrugs that target organic cation/carnitine transporter (OCTN2). Twenty-two l-carnitine analogues were evaluated for human organic cation/carnitine transporter (hOCTN2) inhibition; the 3'-hydroxyl group was found to be the only functional group not contributing to l-carnitine interaction with hOCTN2 among the three functional groups on l-carnitine (i.e., 3'-hydroxyl, amine, and carboxylate). The 3'-hydroxyl group on l-carnitine was therefore chosen as the conjugate site. Three drug-l-carnitine conjugates (i.e., valproyl-l-carnitine, naproxen-l-carnitine, and ketoprofen-l-carnitine) were synthesized along with two ketoprofen analogues that incorporated a linker group (glycolic acid or glycine) between ketoprofen and l-carnitine (i.e., ketoprofen-glycolic acid-l-carnitine and ketoprofen-glycine-l-carnitine). These potential prodrugs were evaluated for their in vitro inhibition, transport, and metabolism properties. All three drug-l-carnitine conjugates and ketoprofen-glycine-l-carnitine were OCTN2 inhibitors, as well as substrates. For valproyl-l-carnitine, K-i = 155 +/- 19 mu M, K-m = 132 +/- 23 mu M, and normalized J(max) = 0.467 +/- 0.028; for naproxen-l-carnitine, K-i = 5.97 +/- 0.81 mu M, K-m = 257 +/- 57 mu M, and normalized J(max) = 0.141 +/- 0.012; for ketoprofen-l-carnitine, K-i = 82.2 +/- 5.3 mu M, K-m = 77.0 +/- 4.0 mu M, and normalized J(max) = 0.412 +/- 0.015; for ketoprofen-glycine-l-carnitine, K-i = 14.4 +/- 1.4 mu M, K-m = 58.5 +/- 8.7 mu M, and normalized J(max) = 0.0789 +/- 0.0037. Ketoprofen-glycolic acid-l-carnitine was unstable in metabolic buffers and chemical buffers. On the contrary, naproxen-l-carnitine, ketoprofen-l-carnitine, and ketoprofen-glycine-l-carnitine were stable in chemical and metabolic buffers. The results demonstrate the potential of drug-l-carnitine conjugates to serve as prodrugs that target OCTN2. (C) 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3802-3816, 2011