DS86760016

DS86760016 is a potent leucyl-tRNA synthetase (LeuRS) inhibitor with activity against multidrug-resistant (MDR) Gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. DS86760016 inhibits LeuRS enzymes from Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii, with IC₅₀s of 0.38, 0.62, and 0.16 μM, respectively^[1][2]. In Vitro: DS86760016 inhibits some Gram-negative bacteria with an MICs ranging from 0.25 to 2 μg/ml. The MIC of DS86760016 against Gram-positive bacteria is >32 μg/ml. DS86760016 is active against both susceptible and these MDR P. aeruginosa, E. coli, and K. pneumoniae strains, with an MIC₉₀ of 2 μg/ml^[1]. In Vivo: 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_IVs) of 1.5, 0.6, 3.7, and 3.0 μg h kg/ml/mg in mice, rats, monkeys, and dogs, respectively^[1].