Previous studies have identified a series of imidazo[1,2-a]pyridine (IZP) derivatives as potent allosteric inhibitors of HIV-1 integrase (ALLINIs) and virus infection in cell culture. However, IZPs were also found to be relatively potent activators of the pregnane-X receptor (PXR), raising the specter of induction of CYP-mediated drug disposition pathways. In an attempt to modify PXR activity without affecting anti-HIV-1 activity, rational structure-based design and modeling approaches were used. An X-ray cocrystal structure of (S,S)-1 in the PXR ligand binding domain (LBD) allowed an examination of the potential of rational structural modifications designed to abrogate PXR. The introduction of bulky basic amines at the C-8 position provided macrocyclic IZP derivatives that displayed potent HIV-1 inhibitory activity in cell culture with no detectable PXR transactivation at the highest concentration tested.

先前的研究已经确定了一系列咪唑并[1,2- a ]吡啶（IZP）衍生物作为HIV-1整合酶（ALLINIs）和细胞培养中病毒感染的有效变构抑制剂。但是，也发现IZP是孕烷X受体（PXR）的相对有效激活剂，从而增加了CYP介导的药物处置途径的诱导。为了在不影响抗HIV-1活性的情况下修饰PXR活性，使用了基于结构的合理设计和建模方法。（S，S）-1的X射线共晶体结构PXR配体结合结构域（LBD）中的SNP允许检查旨在消除PXR的合理结构修饰的潜力。在C-8位置引入笨重的碱性胺可提供大环IZP衍生物，该衍生物在细胞培养中显示出有效的HIV-1抑制活性，在最高测试浓度下未检测到PXR反式激活。