Taoda Yoshiyuki, Akiyama Toshiyuki, Tomita Kenji, Fujiwara-Kitamura Misato, Tamura Yoshinori, Kawasuji Takashi, Matsuoka Eriko, Akihisa Erika, Seki Takahiro, Yoshinaga Tomokazu
Shionogi Pharmaceutical Research Center, Shionogi & Company, Limited, 1-1, Futabacho, 3-chome, Toyonaka 561-0825, Japan.
Shionogi Pharmaceutical Research Center, Shionogi & Company, Limited, 1-1, Futabacho, 3-chome, Toyonaka 561-0825, Japan.
Bioorg Med Chem Lett. 2022 May 15;64:128664. doi: 10.1016/j.bmcl.2022.128664. Epub 2022 Mar 8.
We have been conducting exploratory research to develop human immunodeficiency virus type-1 (HIV-1) integrase-LEDGF/p75 allosteric inhibitors (INLAIs). Here, we report on a newly designed compound with a tricyclic scaffold that shows promise as an inhibitor. Various scaffolds were synthesized by intramolecular direct arylation reaction to fix the position of a lipophilic side chain required for antiviral activity. Among these, the compound having an N-mesyl dihydrophenanthridine ring showed the best antiviral activity. Compound 42i, prepared by side chain optimization of the C-4 and C-6 positions, exhibited high antiviral activity against wild-type (WT) and the T174I mutant (EC (WT) = 4.6 nM, EC (T174I) = 83 nM) with a good PK profile. Based on co-crystal structural analysis of compound 42i and WT HIV-1 IN CCD, we discuss the interaction important for high antiviral activity.
我们一直在进行探索性研究，以开发1型人类免疫缺陷病毒（HIV-1）整合酶-LEDGF/p75变构抑制剂（INLAIs）。在此，我们报告一种新设计的具有三环骨架的化合物，它有望成为一种抑制剂。通过分子内直接芳基化反应合成了各种骨架，以固定抗病毒活性所需的亲脂性侧链的位置。其中，具有N-甲磺酰基二氢菲啶环的化合物表现出最佳的抗病毒活性。通过对C-4和C-6位进行侧链优化制备的化合物42i，对野生型（WT）和T174I突变体表现出高抗病毒活性（EC（WT）=4.6 nM，EC（T174I）=83 nM），且具有良好的药代动力学特征。基于化合物42i与野生型HIV-1整合酶在CCD中的共晶体结构分析，我们讨论了对高抗病毒活性重要的相互作用。
