| 描述 | DS86760016 is a highly effective inhibitor of leucyl-tRNA synthetase (LeuRS), demonstrating potent activity against multidrug-resistant (MDR) Gram-negative bacteria including Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Notably, DS86760016 effectively inhibits LeuRS enzymes derived from Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii, exhibiting IC50 values of 0.38 μM, 0.62 μM, and 0.16 μM, respectively. |
| 体内活性 | DS86760016 (7.5-220 mg/kg; s.c.; q6h for 7 days) shows moderate spontaneous resistance (FSR)[1]. The pharmacokinetic (PK) parameters of DS86760016 in mouse, rat, monkey, and dog plasma by the intravenous (i.v.) route are test. DS86760016 shows lower intravenous plasma clearances (CL p ) of 11, 29, 5.6, and 4.5 ml/min/kg in mouse, rat, monkey, and dog plasma, respectively. The plasma half-lives (t 1/2 ) for DS86760016 are 1.9, 1.5, 8.6, and 8.3 h in mice, rats, monkeys, and dogs, respectively. The lower plasma clearance resulted in higher plasma exposures for DS86760016, with dose-normalized areas under the curve after i.v. administration (DNAUC IV s) of 1.5, 0.6, 3.7, and 3.0 μg h kg/ml/mg in mice, rats, monkeys, and dogs, respectively[1]. Animal Model: Immunocompetent female Swiss Webster mice (urinary tract infection, UTI model)[1]Dosage: 7.5, 30, 220 mg/kg Administration: S.c.; q6h for 7 days Result: Bacteria resistant to DS86760016 were detected in a few animals after 1 day of treatment at doses of 7.5 and 30 mg/kg q6h; however, no resistant bacteria were detected at these doses after 7 days of treatment. No resistance was observed in any of the mice treated at a dose of 220 mg/kg q6h. |