卤代2,6 - 二芳基吡啶胺作为新型HIV-1非核苷逆转录酶抑制剂的抗病毒效力和亲脂性的优化
Optimization of the antiviral potency and lipophilicity of halogenated 2,6-diarylpyridinamines as a novel class of HIV-1 NNRTIS.
作者信息
Wu Zhi-Yuan, Liu Na, Qin Bingjie, Huang Li, Yu Fei, Qian Keduo, Morris-Natschke Susan L, Jiang Shibo, Chen Chin Ho, Lee Kuo-Hsiung, Xie Lan
机构信息
Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing, 100850 (China).
出版信息
ChemMedChem. 2014 Jul;9(7):1546-55. doi: 10.1002/cmdc.201400075. Epub 2014 Jun 4.
Abstract
Nineteen new halogenated diarylpyridinamine (DAPA) analogues modified at the phenoxy C-ring were synthesized and evaluated for anti-HIV activity and certain drug-like properties. Ten compounds showed high anti-HIV activity (EC50 <10 nM). In particular, (E)-6-(2''-bromo-4''-cyanovinyl-6''-methoxy)phenoxy-N(2) -(4'-cyanophenyl)pyridin-2,3-diamine (8 c) displayed low-nanomolar antiviral potency (3-7 nM) against wild-type and drug-resistant viral strains bearing the E138K or K101E mutations, which are associated with resistance to rilvipirine (1 b). Compound 8 c exhibited much lower resistance fold changes (RFC: 1.1-2.1) than 1 b (RFC: 11.8-13.0). Compound 8 c also exhibited better metabolic stability (in vitro half-life) than 1 b in human liver microsomes, possessed low lipophilicity (clog D: 3.29; measured log P: 3.31), and had desirable lipophilic efficiency indices (LE>0.3, LLE>5, LELP<10). With balanced potency and drug-like properties, 8 c merits further development as an anti-HIV drug candidate.
摘要
合成了19种在苯氧基C环上修饰的新型卤代二芳基吡啶胺（DAPA）类似物，并对其抗HIV活性和某些类药性质进行了评估。10种化合物表现出高抗HIV活性（EC50<10 nM）。特别地，（E）-6-（2''-溴-4''-氰基乙烯基-6''-甲氧基）苯氧基-N(2) -（4'-氰基苯基）吡啶-2,3-二胺（8 c）对携带E138K或K101E突变的野生型和耐药病毒株显示出低纳摩尔抗病毒效力（3-7 nM），这些突变与对利匹韦林（1 b）的耐药性有关。化合物8 c的耐药倍数变化（RFC：1.1-2.1）远低于1 b（RFC：11.8-13.0）。在人肝微粒体中，化合物8 c还表现出比1 b更好的代谢稳定性（体外半衰期），具有低亲脂性（clog D：3.29；实测log P：3.31），并具有理想的亲脂效率指数（LE>0.3, LLE>5, LELP<10）。由于具有平衡的效力和类药性质，8 c作为抗HIV药物候选物值得进一步开发。
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