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首页> 外文期刊>The Journal of Antibiotics: An International Journal >Novel prodrugs of meropenem with two lipophilic promoieties: synthesis and pharmacokinetics.
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Novel prodrugs of meropenem with two lipophilic promoieties: synthesis and pharmacokinetics.

机译：美罗培南的新型前药具有两个亲脂性：合成和药代动力学。

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摘要

To improve the oral absorption of meropenem (MEPM), we synthesized and evaluated a series of its double-promoiety prodrugs, in which lipophilic promoieties were introduced into carboxyl and pyrrolidinyl groups. Among these prodrugs, pivaloyloxymethyl (1R,5S,6S)-2-[(3S,5S)-5-(N,N-dimethylcarbamoyl)-1-(isobutyryloxymethyloxycarbonyl )pyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (4) and 1-ethylpropyloxycarbonyloxymethyl (1R,5S,6S)-2-[(3S,5S)-5-(N,N-dimethylcarbamoyl)-1-(isobutyryloxymethyloxycarbonyl )pyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (8) were chosen for further evaluation. Compounds 4 and 8 were well absorbed after oral administration to rats and beagles (bioavailability 18.2-38.4%), and expected to show potent therapeutic efficacy in patients infected with various pathogens, such as penicillin-resistant S. pneumoniae and beta-lactamase-negative ampicillin-resistant H. influenzae.
机译：为了改善美洛培南（MEPM）的口服吸收，我们合成并评估了其双促性前药系列，其中将亲脂性促成基引入到羧基和吡咯烷基中。在这些前药中，新戊酰氧基甲基（1R，5S，6S）-2-[（3S，5S）-5-（N，N-二甲基氨基甲酰基）-1-（异丁酰氧基甲基氧基羰基）吡咯烷-3-基硫基] -6-[（1R） -1-羟乙基] -1-甲基卡宾-2-em-3-羧酸盐（4）和1-乙基丙氧基羰基氧基甲基（1R，5S，6S）-2-[（3S，5S）-5-（N，N-二甲基氨基甲酰基）选择-1-（异丁酰氧基甲氧基羰基）吡咯烷-3-基硫基] -6-[（（1R）-1-羟乙基] -1-甲基咔啉-2-em-3-羧酸酯（8）进行进一步评估。口服给予大鼠和比格犬后，化合物4和8吸收良好（生物利用度18.2-38.4％），并有望对感染各种病原体（如耐青霉素的肺炎链球菌和β-内酰胺酶阴性）的患者显示出有效的治疗功效。耐氨苄青霉素的流感嗜血杆菌。

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