Development of fluorine-substituted NH(2)-biphenyl-diarylpyrimidines as highly potent non-nucleoside reverse transcriptase inhibitors: Boosting the safety and metabolic stability.
Development of fluorine-substituted NH(2)-biphenyl-diarylpyrimidines as highly potent non-nucleoside reverse transcriptase inhibitors: Boosting the safety and metabolic stability.
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开发氟取代的NH2-联苯二芳基嘧啶作为高效非核苷逆转录酶抑制剂：提高安全性和代谢稳定性
DOI：
10.1016/j.apsb.2022.08.017
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发表时间：
2023-03
影响因子：
14.5
通讯作者：
Chen, Fener
中科院分区：
文献类型：
--
作者：
Jin, Xin;Wang, Shuai;Zhao, Limin;Huang, Wenjuan;Zhang, Yinxiang;Pannecouque, Christophe;De Clercq, Erik;Meng, Ge;Piao, Huri;Chen, Fener
我们最近对非核苷类逆转录酶抑制剂的研究发现了一种对WT HIV-1高效的化合物JK-4b(EC_(50)=11.0nmol/L)，但人肝微粒体代谢稳定性差(t_(1/2)=114.6μ)和选择性不足(SI_(50)=0.2059)和高细胞毒性(CC_(50)=22.08 nmol/L)仍然是与JK-4b相关的主要问题。本工作致力于在JK-4b的联苯环上引入氟，从而发现了一系列新的氟取代的NH_2-联苯-二芳基嘧啶类化合物，对WT HIV-1毒株具有显著的抑制活性(EC_(50)=11.8-349nmol/L)。与JK-4b相比，最好的化合物5t(EC_(50)=11.8μ/L，CC_(50)=11,117 nmol/L)的选择性(SI_(50)=66,443)是JK-4B的32倍，对临床上的多个突变株，如L100I，K103N，E138K和Y181C显示出显著的效力。5t的代谢稳定性也显著提高(t1/2=0.74.52×10-6)，约为人肝微粒体中JK-4b的5倍(t1/2=0.14×10-6×10-6)。5T在人和猴血浆中均具有良好的稳定性。体外对CYP酶和HERG无明显抑制作用。单次给药急性毒性试验未引起小鼠死亡或明显的病理损伤。这些发现为进一步开发5T作为候选药物铺平了道路。在本研究中，我们报道了一系列具有显著抗HIV活性的氟取代的NH2-联苯-二芳基嘧啶类化合物，其中5T表现出显著的药效性。
Our recent studies for nonnucleoside reverse transcriptase inhibitors identified a highly potent compound JK-4b against WT HIV-1 (EC50 = 1.0 nmol/L), but the poor metabolic stability in human liver microsomes (t1/2 = 14.6 min) and insufficient selectivity (SI = 2059) with high cytotoxicity (CC50 = 2.08 μmol/L) remained major issues associated with JK-4b. The present efforts were devoted to the introduction of fluorine into the biphenyl ring of JK-4b, leading to the discovery of a novel series of fluorine-substituted NH2-biphenyl-diarylpyrimidines with noticeable inhibitory activity toward WT HIV-1 strain (EC50 = 1.8–349 nmol/L). The best compound 5t in this collection (EC50 = 1.8 nmol/L, CC50 = 117 μmol/L) was 32-fold in selectivity (SI = 66,443) compared to JK-4b and showed remarkable potency toward clinically multiple mutant strains, such as L100I, K103N, E138K, and Y181C. The metabolic stability of 5t was also significantly improved (t1/2 = 74.52 min), approximately 5-fold higher than JK-4b in human liver microsomes (t1/2 = 14.6 min). Also, 5t possessed good stability in both human and monkey plasma. No significant in vitro inhibition effect toward CYP enzyme and hERG was observed. The single-dose acute toxicity test did not induce mice death or obvious pathological damage. These findings pave the way for further development of 5t as a drug candidate. In the present study, we reported a series of fluorine-substituted NH2-biphenyl-diarylpyrimidines with noticeable anti-HIV activity, of which 5t exhibited significantly improved druggability.
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DOI：
10.1016/j.gresc.2020.06.001
发表时间：
2020-06-01
期刊：
GREEN SYNTHESIS AND CATALYSIS
影响因子：
--
作者：
Deng, Qinyue;Zheng, Qingshu;Tu, Tao
通讯作者：
Tu, Tao
影响因子：
7.3
作者：
Kang, Dongwei;Feng, Da;Zhan, Peng
通讯作者：
Zhan, Peng
影响因子：
7.3
作者：
Sang, Yali;Han, Sheng;Chen, Fener
通讯作者：
Chen, Fener
影响因子：
4.6
作者：
Godinho, Ana L. A.;Martins, Ines L.;Antunes, Alexandra M. M.
通讯作者：
Antunes, Alexandra M. M.
DOI：
10.1016/j.gresc.2021.10.002
发表时间：
2022-02-01
期刊：
GREEN SYNTHESIS AND CATALYSIS
影响因子：
--
作者：
Gong, Bozhen;Zhu, Haibo;Le, Zhanggao
通讯作者：
Le, Zhanggao