Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Yanbian University College of Pharmacy, Yanbian University, 977 Gongyuan Road, Yanji, Jilin Province, 133002, China; Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai, 200433, China.
Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai, 200433, China.
Eur J Med Chem. 2022 Oct 5;240:114581. doi: 10.1016/j.ejmech.2022.114581. Epub 2022 Jun 30.
Adding to past success in developing non-nucleoside reverse transcriptase inhibitors (NNRTIs), we report herein our efforts to optimize an FDA-approved NNRTI, doravirine, into a series of novel biphenyl-substituted pyridone derivatives. A strategy focused on harnessing the X-ray crystal structure of doravirine, coupled with computer simulations, to guide the design of conformationally constrained analogs led to the discovery of ZLM-66, which provided comparable inhibitory potency to doravirine against wild-type HIV-1 (EC = 13 nM) and various single/double mutant strains. ZLM-66 possessed acceptable cytotoxicity and selectivity index. In vivo profiling indicated that ZLM-66 exhibited excellent pharmacokinetics with significantly improved oral bioavailability (F = 140.24%) and a more favorable half-life (T = 8.45 h), compared to that of doravirine (F = 57%, T = 4.4 h). In addition, ZLM-66 did not cause significant inhibition of CYP and hERG (>200 μM), as well as acute toxicity and tissue damage at a dose of 1.2 g/kg. Therefore, ZLM-66 can be used as a lead compound to further guide the development of orally active biphenyl-containing doravirine analogs for HIV therapy.
在过去成功开发非核苷类逆转录酶抑制剂（NNRTIs）的基础上，我们在此报告了我们将一种已获得 FDA 批准的 NNRTI，即多拉韦林，优化为一系列新型联苯取代吡啶酮衍生物的努力。一项专注于利用多拉韦林的 X 射线晶体结构，结合计算机模拟，指导设计构象受限类似物的策略，导致发现了 ZLM-66，它对野生型 HIV-1（EC = 13 nM）和各种单/双突变株具有与多拉韦林相当的抑制效力。ZLM-66 具有可接受的细胞毒性和选择性指数。体内特征表明，与多拉韦林（F = 57%，T = 4.4 h）相比，ZLM-66 具有出色的药代动力学特性，显著提高了口服生物利用度（F = 140.24%）和半衰期（T = 8.45 h）。此外，ZLM-66 对 CYP 和 hERG 的抑制作用不明显（>200 μM），在 1.2 g/kg 剂量下也没有引起明显的急性毒性和组织损伤。因此，ZLM-66 可用作先导化合物，进一步指导具有口服活性的含联苯多拉韦林类似物的开发，用于 HIV 治疗。
