Crystalline 1 (TAK-599) is a novel N-phosphono prodrug of anti-methicillin-resistant Staphylococcus aureus (MRSA) cephalosporin 2a (T-91825) that has high affinity for penicillin-binding protein (PBP) 2' (IC(50); 0.90 microg/mL) and shows potent in vitro anti-MRSA activity (MIC against MRSA N133; 1.56 microg/mL), comparable to that of vancomycin (1.56 microg/mL). Although 2a had insufficient water solubility (2.3 mg/mL) for parenteral administration, 1 showed excellent water solubility (>100 mg/mL, pH 7) as well as good chemical stability in the solid state and solution. In pharmacokinetic studies, when 1 was administered intravenously to rats and monkeys, it was rapidly converted into 2a in the blood. These results show that 1 (TAK-599) is a highly promising parenteral cephalosporin targeted for MRSA infection.

中文翻译：

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TAK-599，一种抗MRSA头孢菌素T-91825的新型N-膦酰基型前药：合成，理化和药理特性。

结晶1（TAK-599）是抗甲氧西林金黄色葡萄球菌（MRSA）头孢菌素2a（T-91825）的新型N膦酰基前药，对青霉素结合蛋白（PBP）2'（IC（50 ）; 0.90 microg / mL）并显示出强大的体外抗MRSA活性（MICRO MRSA N133; 1.56 microg / mL），与万古霉素相当（1.56 microg / mL）。尽管2a的肠胃外给药水溶解度（2.3 mg / mL）不足，但1a表现出优异的水溶性（> 100 mg / mL，pH 7），以及在固态和溶液中的良好化学稳定性。在药代动力学研究中，当向大鼠和猴子静脉注射1时，血液中的1a迅速转化为2a。这些结果表明1（TAK-599）是针对MRSA感染的高度有前景的肠胃外头孢菌素。