Title of article :
TAK-599, a novel N-Phosphono type prodrug of anti-MRSA cephalosporin T-91825: synthesis, physicochemical and pharmacological properties Original Research Article
Author/Authors :
Tomoyasu Ishikawa، نويسنده , , Nobuyuki Matsunaga، نويسنده , , Hiroyuki Tawada، نويسنده , , Noritaka Kuroda، نويسنده , , Yutaka Nakayama، نويسنده , , Yukio Ishibashi، نويسنده , , Mitsumi Tomimoto، نويسنده , , Yukihiro Ikeda، نويسنده , , Yoshihiko Tagawa، نويسنده , , Yuji Iizawa، نويسنده , , Kenji Okonogi، نويسنده , , Shohei Hashiguchi، نويسنده , , Akio Miyake، نويسنده ,
Abstract :
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′ (IC50; 0.90 μg/mL) and shows potent in vitro anti-MRSA activity (MIC against MRSA N133; 1.56 μg/mL), comparable to that of vancomycin (1.56 μg/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.
