State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China.
Department of Pharmaceutical and Bioengineering, School of Chemical Engineering, Sichuan University, Chengdu, Sichuan, China.
Antimicrob Agents Chemother. 2018 Jun 26;62(7). doi: 10.1128/AAC.02375-17. Print 2018 Jul.
Tuberculosis is a major global health problem, and the emergence of multidrug-resistant and extensively drug-resistant strains has increased the difficulty of treating this disease. Among the novel antituberculosis drugs in the pipeline, decaprenylphosphoryl-beta-d-ribose-2-epimerase (DprE1) inhibitors such as BTZ043 and pBTZ169 exhibited extraordinary antituberculosis potency. Here, the metabolites of the new DprE1 inhibitor SKLB-TB1001 and its inhibition of cytochrome P450 isoforms and plasma protein binding (PPB) were studied. The results showed that rapid transformation and high PPB resulted in inadequate exposure and thus led to the moderate potency of SKLB-TB1001 This study provided explanations for the discrepant potency of this scaffold and Meanwhile, it also provides a rationale for lead optimization of this very promising scaffold of antituberculosis agents to prevent them from being metabolized, thus improving their exposure .
结核病是一个全球性的重大健康问题，耐多药和广泛耐药菌株的出现增加了治疗这种疾病的难度。在新型抗结核药物中，二烯丙基磷酸-β-D-核糖-2-差向异构酶（DprE1）抑制剂，如 BTZ043 和 pBTZ169，表现出了非凡的抗结核活性。在这里，研究了新型 DprE1 抑制剂 SKLB-TB1001 的代谢产物及其对细胞色素 P450 同工酶和血浆蛋白结合（PPB）的抑制作用。结果表明，快速转化和高 PPB 导致了暴露不足，从而导致了 SKLB-TB1001 的中等活性。这项研究解释了这个支架的效力差异，并为该有前途的抗结核药物支架的先导优化提供了依据，以防止它们被代谢，从而提高它们的暴露度。
