Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties
Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties
复制标题
DOI：
10.1021/acs.jmedchem.0c00117
复制
发表时间：
2020-05-14
影响因子：
7.3
通讯作者：
Zhan, Peng
中科院分区：
文献类型：
--
作者：
Kang, Dongwei;Feng, Da;Zhan, Peng
用于艾滋病治疗的有效 NNRTI 的开发通常会遇到耐药突变的快速产生，这成为有效抗 HIV 治疗的主要障碍。采用基于结构的生物电子等排策略，设计并合成了一系列哌啶取代的噻吩[2,3-d]嘧啶衍生物。化合物 9a 产生了最大的效力，对所有测试的 NNRTI 抗性 HIV-1 菌株表现出比 ETR 显着更好的抗 HIV-1 活性。此外，还评估了 9a 和其他 NRTI 对不同选定 HIV-1 毒株的表型（交叉）耐药性。正如预期的那样，突变体 9a(res) 菌株没有观察到针对 NRTI（AZT 和 PMPA）的表型交叉耐药性。此外，9a 还被发现具有改善的溶解度、较低的 CYP 敏感性和 hERG 抑制作用。值得注意的是，9a 在大鼠中表现出最佳的药代动力学特性（F = 37.06%），在小鼠中表现出安全性（LD50 > 2000 mg/kg），这凸显了 9a 作为一种有前途的抗 HIV-1 候选药物。
The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9a(res) strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.