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基于结构设计的新型异环替代ATDP类似物作为非核糖逆转录酶抑制剂,具有改进的选择性和可溶性

Li-Min Zhao^1,2,3, Christophe Pannecouque⁴, Erik De Clercq⁴

¹Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Yanbian University College of Pharmacy, Yanbian University, Yanji 133002, China.

Acta pharmaceutica Sinica. B

|December 4, 2023

概括

研究人员开发了一种新型异环基替代ATDP衍生物,7w,可显著提高HIV治疗的选择性和溶解性. 这种有前途的非核酸逆转录酶抑制剂 (NNRTI) 显示出对各种HIV菌株的强大活性和有利的安全性.

科学领域:

药用化学医学化学
病毒学病毒学
药理学药理学是指药理学的学科.

背景情况:

开发ZLM-66,一种双-ATDP非核酸逆转录酶抑制剂 (NNRTI).
鉴定了以前的NNRTI候选物的选择性和溶解性的局限性.

研究的目的:

设计和合成新型异环基替代ATDP衍生物.
与现有的NNRTI相比,提高选择性和可溶性.
评估HIV治疗新类型的疗效和安全性.

主要方法:

合成了一系列新的异环替代ATDP衍生物.
将ZLM-66的双基部分替换为具有较低脂友性的异环基.
评估的选择性 (SI),溶解性 (S) 和野生型和突变HIV-1菌株的抑制.
评估了安全性概况,包括CYP和hERG相互作用,以及药物动力学特性 (大鼠口服生物利用率).

主要成果:

与ZLM-66.6相比,模拟7w显示了显著增强的选择性 (SI = 12,497.73) 和可溶性 (S = 4472 μg/mL).
7w表现出对野生型HIV-1和关键突变菌株 (K103N,L100I,Y181C,E138K,K103N+Y181C) 的低纳米分子抑制.
7w在老鼠中显示出良好的安全性 (对CYP/hERG不敏感,没有死亡率/病理损伤) 和良好的口服生物可用性 (F=27.1%).

结论:

新型异环基替代ATDP衍生物7w代表了HIV治疗的有希望的候选者.
7w提供卓越的选择性,可溶性和强大的抗病毒活性.
良好的安全性和药理动力学特征支持7w在艾滋病毒治疗中的进一步临床开发.

关键词:

在ATDP中,我们可以使用ATDP.艾滋病病毒-1 艾滋病病毒-1 没有NNRTIs的NNRTI 皮里顿是什么皮里顿是什么美国美国美国美国美国

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