We are continuing our concerted effort to optimize our first lead entry antagonist, NBD-11021, which targets the Phe43 cavity of the HIV-1 envelope glycoprotein gp120, to improve antiviral potency and ADMET properties. In this report, we present a structure-based approach that helped us to generate working hypotheses to modify further a recently reported advanced lead entry antagonist, NBD-14107, which showed significant improvement in antiviral potency when tested in a single-cycle assay against a large panel of Env-pseudotyped viruses. We report here the synthesis of twenty-nine new compounds and evaluation of their antiviral activity in a single-cycle and multi-cycle assay to derive a comprehensive structure-activity relationship (SAR). We have selected three inhibitors with the high selectivity index for testing against a large panel of 55 Env-pseudotyped viruses representing a diverse set of clinical isolates of different subtypes. The antiviral activity of one of these potent inhibitors, 55 (NBD-14189), against some clinical isolates was as low as 63 nM. We determined the sensitivity of CD4-binding site mutated-pseudoviruses to these inhibitors to confirm that they target HIV-1 gp120. Furthermore, we assessed their ADMET properties and compared them to the clinical candidate attachment inhibitor, BMS-626529. The ADMET data indicate that some of these new inhibitors have comparable ADMET properties to BMS-626529 and can be optimized further to potential clinical candidates.

我们正在继续共同努力，以优化我们的第一个铅进入拮抗剂NBD-11021，其靶向HIV-1包膜糖蛋白gp120的Phe43腔，以提高抗病毒效力和ADMET特性。在本报告中，我们提出了一种基于结构的方法，该方法帮助我们产生了可行的假设，以进一步修改最近报道的先进的铅进入拮抗剂NBD-14107，该抑制剂在单周期试验中针对抗大型的Env假型病毒。我们在这里报告了29种新化合物的合成及其在单周期和多周期分析中的抗病毒活性评估，以得出全面的构效关系（SAR）。我们选择了三种具有高选择性指数的抑制剂，以针对代表一组不同亚型临床分离株的55种Env假型病毒进行测试。这些有效抑制剂之一的抗病毒活性，55（NBD-14189）对某些临床分离株的抗药性低至63 nM。我们确定了CD4结合位点突变型假病毒对这些抑制剂的敏感性，以确认它们靶向HIV-1 gp120。此外，我们评估了它们的ADMET特性，并将其与临床候选附着抑制剂BMS-626529进行了比较。ADMET数据表明，这些新型抑制剂中的某些具有与BMS-626529相当的ADMET特性，可以针对潜在的临床候选者进行进一步优化。