Sang Ya-Li, Pannecouque Christophe, De Clercq Erik, Wang Shuai, Chen Fen-Er
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.
J Med Chem. 2023 Apr 13;66(7):4755-4767. doi: 10.1021/acs.jmedchem.2c01900. Epub 2023 Mar 30.
To enhance the anti-resistance efficacy of our previously reported non-nucleoside reverse transcriptase inhibitor (NNRTI) , a series of novel biphenyl-DAPY derivatives were developed using the fragment-hopping strategy. Most of the compounds exhibited remarkably improved anti-HIV-1 potency. The most active compound proved to be exceptionally potent against the wild-type HIV-1 (EC = 2.3 nM) and five mutant strains, such as K103N (EC = 8 nM) and E138K (EC = 6 nM), significantly better than . The new DAPY analogue was 8-fold less cytotoxic and had a 17-fold higher selectivity index (CC = 40.77 μM, SI > 17391) than etravirine and rilpivirine. Also, it displayed favorable pharmacokinetic properties with an oral bioavailability of 31.19% and weak sensitivity toward both CYP and hERG. No apparent acute toxicity (2 g/kg) and tissue damage occurred. These findings will further expand the possibility of successfully identifying biphenyl-DAPY analogues as highly potent, safe, and orally active NNRTIs for HIV treatment.
为提高我们之前报道的非核苷类逆转录酶抑制剂（NNRTI）的抗耐药功效，采用片段跳跃策略开发了一系列新型联苯 - DAPY衍生物。大多数化合物表现出显著提高的抗HIV - 1效力。最具活性的化合物对野生型HIV - 1（EC = 2.3 nM）和五种突变株（如K103N（EC = 8 nM）和E138K（EC = 6 nM））具有极高的效力，明显优于……。新的DAPY类似物的细胞毒性比依曲韦林和利匹韦林低8倍，选择性指数高17倍（CC = 40.77 μM，SI > 17391）。此外，它具有良好的药代动力学性质，口服生物利用度为31.19%，对CYP和hERG的敏感性较弱。未出现明显的急性毒性（2 g/kg）和组织损伤。这些发现将进一步扩大成功鉴定联苯 - DAPY类似物作为高效、安全且口服活性的HIV治疗NNRTIs的可能性。
