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TAK-599, a novel N-phosphono type prodrug of anti-MRSA cephalosporin T-91825: synthesis, physicochemical and pharmacological properties.
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2003-05-09 , DOI: 10.1016/s0968-0896(03)00126-3 Tomoyasu Ishikawa 1 , Nobuyuki Matsunaga , Hiroyuki Tawada , Noritaka Kuroda , Yutaka Nakayama , Yukio Ishibashi , Mitsumi Tomimoto , Yukihiro Ikeda , Yoshihiko Tagawa , Yuji Iizawa , Kenji Okonogi , Shohei Hashiguchi , Akio Miyake
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2003-05-09 , DOI: 10.1016/s0968-0896(03)00126-3 Tomoyasu Ishikawa 1 , Nobuyuki Matsunaga , Hiroyuki Tawada , Noritaka Kuroda , Yutaka Nakayama , Yukio Ishibashi , Mitsumi Tomimoto , Yukihiro Ikeda , Yoshihiko Tagawa , Yuji Iizawa , Kenji Okonogi , Shohei Hashiguchi , Akio Miyake
Affiliation
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:
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。
更新日期:2019-11-01
中文翻译:
![](https://scdn.x-mol.com/jcss/images/paperTranslation.png)
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。