Discovery of a Potent HIV Integrase Inhibitor that Leads to a Prodrug with Significant anti-HIV Activity.
Discovery of a Potent HIV Integrase Inhibitor that Leads to a Prodrug with Significant anti-HIV Activity.
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发现一种有效的 HIV 整合酶抑制剂，可产生具有显着抗 HIV 活性的前药。
DOI：
10.1021/ml2001246
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发表时间：
2011
影响因子：
4.2
通讯作者：
Nair,Vasu
中科院分区：
文献类型：
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作者：
Seo,ByungI;Uchil,VinodR;Okello,Maurice;Mishra,Sanjay;Ma,Xiao-Hui;Nishonov,Malik;Shu,Qingning;Chi,Guochen;Nair,Vasu
全世界在涉及HIV整合酶的药物发现方面的研究工作仅产生了一种化合物，即雷特格韦，该化合物已被批准用于HIV/AIDS的临床用途。由于耐药性、毒性和药物间相互作用是所有类别抗HIV药物反复出现的问题，因此发现新型整合酶抑制剂仍然是一个重大的科学挑战。我们设计了一种领先的HIV-1链转移（ST）抑制剂（IC 5070 nM），战略性地组装在吡啶酮支架上。对该母体化合物进行了重点结构-活性研究，得到了显著更有效的ST抑制剂2（IC 506 ± 3 nM）。化合物2在合并的人肝微粒体中表现出良好的稳定性。它还显示了一个特别有利的配置文件方面的关键人类细胞色素P450（CYP）同工酶和人类UDP葡萄糖醛酸转移酶（UGT）。前体药物2，即，化合物10具有显著的抗HIV-1活性（EC 509 ± 4 nM，CC 50135 ± 7 μM，治疗指数= 15000）。
Worldwide research efforts in drug discovery involving HIV integrase have produced only one compound, raltegravir, that has been approved for clinical use in HIV/AIDS. As resistance, toxicity, and drug–drug interactions are recurring issues with all classes of anti-HIV drugs, the discovery of novel integrase inhibitors remains a significant scientific challenge. We have designed a lead HIV-1 strand transfer (ST) inhibitor (IC5070 nM), strategically assembled on a pyridinone scaffold. A focused structure–activity investigation of this parent compound led to a significantly more potent ST inhibitor,2(IC506 ± 3 nM). Compound2exhibits good stability in pooled human liver microsomes. It also displays a notably favorable profile with respect to key human cytochrome P450 (CYP) isozymes and human UDP glucuronosyl transferases (UGTs). The prodrug of inhibitor2, i.e., compound10, was found to possess remarkable anti-HIV-1 activity in cell culture (EC509 ± 4 nM, CC50135 ± 7 μM, therapeutic index = 15 000).