Disposition and Metabolism of GSK2251052 in Humans: A Novel Boron-Containing Antibiotic

Abstract

ABSTRACT(S)-3-(Aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy-1,3-dihydro-2,1-benzoxaborole (GSK2251052) is a novel boron-containing antibiotic that inhibits bacterial leucyl tRNA synthetase, and that has been in development for the treatment of serious Gramnegative infections. In this study, six healthy adult male subjects received a single i.v. dose of [ 14 C]GSK2251052, 1500 mg infused over 1 hour. Blood, urine, and feces were collected over an extended period of 14 days, and accelerator mass spectrometry was used to quantify low levels of radioactivity in plasma at later time points to supplement the less-sensitive liquid scintillation counting technique. An excellent mass balance recovery was achieved representing a mean total of 98.2% of the dose, including 90.5% recovered in the urine. Pharmacokinetic analysis demonstrated that radioactivity was moderately associated with the blood cellular components, and together with GSK2251052, both were highly distributed into tissues. The parent compound had a much shorter half-life than total radioactivity in plasma, approximately 11.6 hours compared with 96 hours. GSK2251052 and its major metabolite M3, which resulted from oxidation of the propanol side chain to the corresponding carboxylic acid, comprised the majority of the plasma radioactivity, 37 and 53% of the area under the plasma versus time concentration curve from time zero to infinity, respectively. Additionally, M3 was eliminated renally, and was demonstrated to be responsible for the long plasma radioactivity elimination half-life. A combination of in vitro metabolism experiments and a pharmacokinetic study in monkeys with the inhibitor 4-methylpyrazole provided strong evidence that alcohol dehydrogenase, potentially in association with aldehyde dehydrogenase, is the primary enzyme involved in the formation of the M3 metabolite.

In Vitro and In Vivo Activities of DS86760016, a Novel Leucyl-tRNA Synthetase Inhibitor for Gram-Negative Pathogens

“…Only 8.6% of the parent compound was excreted in monkey urine compared to 21.7% of its M3 metabolite (16). A similar trend was observed in humans, with 28.9% of the parent compound and 43.8% of M3 excreted in human urine (17). This metabolism had reduced the effective concentration of active GSK2251052 in human urine.…”

“…DS86760016 was metabolically stable, with its unmetabolized form detected as a major component in monkey plasma, urine, and bile, and two putative metabolites, M1 (deborylated form) and M2 (N-acetylated form), were detected as minor components. In contrast, GSK2251052 was predominantly metabolized to metabolite M3, resulting from oxidation of the propanol side chain to the corresponding carboxylic acid derivative (16,17). In addition to M3, three other minor metabolites of GSK2251052 were identified in monkey samples: M1, which results from deboronation and oxidation of the propanol side chain, M2 (deboronation), and M7 (N-acetylated M3) (Fig.…”

Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles

“…In addition to the oxidative deamination by AO-TbALDH3, we also observed an oxidative deboronation process, which has also been described elsewhere, especially in host plasma, for divergent classes of benzoxaboroles, where it accounts for a compromise in the efficacy of these compounds [ 52 , 53 ]. Our observation raises a possibility that the oxidative enzymes in plasma such as AOs could be responsible for this oxidative deboronation reaction, therefore providing a possible route for improving the efficacy of benzoxaboroles in general.…”

Antimalarial Benzoxaboroles Target Plasmodium falciparum Leucyl-tRNA Synthetase

“…Second, the compounds were active against murine malaria with once-daily dosing. Third, the safety of other benzoxaboroles has been demonstrated, with extensive in vitro and in vivo toxicology studies and progression to trials in humans (22,48,49). Fourth, AN6426 and related benzoxaboroles are easy to synthesize, requiring a 4-to 6-step scheme starting from inexpensive reagents (50).…”