Pharmacokinetics and in vivo antistaphylococcal efficacy of TXY541, a 1-methylpiperidine-4-carboxamide prodrug of PC190723
Pharmacokinetics and in vivo antistaphylococcal efficacy of TXY541, a 1-methylpiperidine-4-carboxamide prodrug of PC190723
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DOI：
10.1016/j.bcp.2013.10.010
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发表时间：
2013-12-15
影响因子：
5.8
通讯作者：
Pilch, Daniel S.
中科院分区：
文献类型：
--
作者：
Kaul, Malvika;Mark, Lilly;Pilch, Daniel S.
苯甲酰胺衍生物PC 190723是第一个有前途的新类别的FtsZ-定向抗菌剂被确定，表现出有效的抗葡萄球菌活性。然而，该化合物与不良的药物样性质相关。作为开发具有增加的临床实用潜力的FtsZ靶向抗菌剂的持续努力的一部分，我们在本文中描述了TXY 541的药效学、药代动力学、体内抗葡萄球菌功效和哺乳动物细胞毒性，TXY 541是PC 190723的新型1-甲基哌啶-4-甲酰胺前药。发现TXY 541在适于口服和静脉内体内给药的含水酸性媒介物（10 mM柠檬酸盐，pH 2.6）中的溶解度是PC 190723的143倍。在葡萄球菌生长培养基中，TXY 541转化为PC 190723，半衰期约为8小时。在100%小鼠血清中，TXY 541-至-PC 190723的转化要快得多（半衰期约为3 mm），表明血清中前药的转化主要是酶催化的。在小鼠中口服和静脉注射TXY 541的药代动力学分析得出PC 190723转化产物的半衰期为0.56小时，口服生物利用度为29.6%。无论是口服还是静脉给药，TXY 541在体内对甲氧西林敏感和耐甲氧西林沙门氏菌全身感染的小鼠模型均有效。金黄色。TXY 541对哺乳动物细胞的毒理学评估显示可检测到的细胞毒性极小。这里呈现的结果突出了TXY 541作为一种潜在的治疗剂，值得进一步的临床前开发。(C)2013 Elsevier Inc. All rights reserved.
The benzamide derivative PC190723 was among the first of a promising new class of FtsZ-directed antibacterial agents to be identified that exhibit potent antistaphylococcal activity. However, the compound is associated with poor drug-like properties. As part of an ongoing effort to develop FtsZ-targeting antibacterial agents with increased potential for clinical utility, we describe herein the pharmacodynamics, pharmacokinetics, in vivo antistaphylococcal efficacy, and mammalian cytotoxicity of TXY541, a novel 1-methylpiperidine-4-carboxamide prodrug of PC190723. TXY541 was found to be 143-times more soluble than PC190723 in an aqueous acidic vehicle (10 mM citrate, pH 2.6) suitable for both oral and intravenous in vivo administration. In staphylococcal growth media, TXY541 converts to PC190723 with a half-life of approximately 8 h. In 100% mouse serum, the TXY541-to-PC190723 conversion was much more rapid (with a half-life of approximately 3 mm), suggesting that the conversion of the prodrug in serum is predominantly enzyme-catalyzed. Pharmacokinetic analysis of both orally and intravenously administered TXY541 in mice yielded a half-life for the PC190723 conversion product of 0.56 h and an oral bioavailability of 29.6%. Whether administered orally or intravenously, TXY541 was found to be efficacious in vivo in mouse models of systemic infection with both methicillin-sensitive and methicillin-resistant S. aureus. Toxicological assessment of TXY541 against mammalian cells revealed minimal detectable cytotoxicity. The results presented here highlight TXY541 as a potential therapeutic agent that warrants further pre-clinical development. (C) 2013 Elsevier Inc. All rights reserved.