Enhancing the therapeutic window for Spectinamide anti-tuberculosis Agents: Synthesis, Evaluation, and activation of phosphate prodrug 3408

IF 2.5 4区 医学 Q3 CHEMISTRY, MEDICINAL Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-08-28 DOI:10.1016/j.bmcl.2024.129934
Jiuyu Liu , Pradeep B. Lukka , Victoria A. Ektnitphong , Keyur R. Parmar , Santosh Wagh , Yan Lu , Robin B. Lee , Dimitri Scherbakov , Han Wang , Matthew D Zimmerman , Bernd Meibohm , Gregory T. Robertson , Vêronique Dartois , Erik C. Böttger , Anne J. Lenaerts , Richard E. Lee
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Abstract

Spectinamides are a novel class of narrow-spectrum antitubercular agents with the potential to treat drug-resistant tuberculosis infections. Spectinamide 1810 has shown a good safety record following subcutaneous injection in mice or infusion in rats but exhibits transient acute toxicity following bolus administration in either species. To improve the therapeutic index of 1810, an injectable prodrug strategy was explored. The injectable phosphate prodrug 3408 has a superior maximum tolerated dose compared to 1810 or Gentamicin. Following intravenous administration in rodents, prodrug 3408 was quickly converted to 1810. The resulting 1810 exposure and pharmacokinetic profile after 3408 administration was identical to equivalent molar amounts of 1810 given directly by intravenous administration. 3408 and the parent 1810 exhibited similar overall efficacy in a BALB/c acute tuberculosis efficacy model. Delivery of 1810 in phosphate prodrug form, therefore, holds the potential to improve further the therapeutic index of an already promising tuberculosis antibiotic.

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提高谱酰胺类抗结核药物的治疗窗口期:磷酸原药 3408 的合成、评估和活化。
光谱酰胺类药物是一类新型窄谱抗结核药物,具有治疗耐药性结核感染的潜力。在对小鼠进行皮下注射或对大鼠进行输注后,1810 号谱酰胺显示出良好的安全性,但在对这两种动物进行栓剂给药后,均表现出短暂的急性毒性。为了提高 1810 的治疗指数,我们探索了一种注射原药策略。与 1810 或庆大霉素相比,可注射的磷酸原药 3408 的最大耐受剂量更高。在啮齿动物体内静脉注射后,原药 3408 会迅速转化为 1810。静脉注射 3408 后,1810 的暴露量和药代动力学特征与直接静脉注射等摩尔量的 1810 完全相同。在 BALB/c 急性结核病疗效模型中,3408 和母体 1810 表现出相似的总体疗效。因此,以磷酸盐原药形式给药的 1810 有可能进一步提高这种已经很有前景的结核病抗生素的治疗指数。
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来源期刊
CiteScore
5.70
自引率
3.70%
发文量
463
审稿时长
27 days
期刊介绍: Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.
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