Discovery of novel, potent, and selective small-molecule CCR5 antagonists as anti-HIV-1 agents: Synthesis and biological evaluation of anilide derivatives with a quaternary ammonium moiety
Discovery of novel, potent, and selective small-molecule CCR5 antagonists as anti-HIV-1 agents: Synthesis and biological evaluation of anilide derivatives with a quaternary ammonium moiety
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DOI：
10.1021/jm9906264
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发表时间：
2000-05-18
影响因子：
7.3
通讯作者：
Fujino, M
中科院分区：
文献类型：
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作者：
Shiraishi, M;Aramaki, Y;Fujino, M
通过使用[I-125]RANTES和CHO/CCR 5细胞对Takeda化学文库进行高通量筛选（HTS）来寻找新的小分子CCR 5拮抗剂，发现了具有季铵或磷部分的先导化合物（A，B），合成这些化合物用于研究新的MCP-1受体拮抗剂。设计、合成了一系列新颖的含季铵基团的苯胺类化合物1，并对其进行了CCR 5拮抗活性的测试。通过对先导化合物进行优化，我们发现N，N-二甲基-N-[4-[2-（4-甲基苯基）-6，7-二氢-5H-苯并环庚烯-8-基]羰基]氨基]苄基]四氢-2H-吡喃-4-氯化铵（1 r，TAK-779）是一种高效和选择性的非肽类CCR 5拮抗剂，在结合试验中的IC 50值为1.4 nM。化合物Ir还抑制MAGI-CCR 5细胞和PBMC中嗜巨噬细胞（M）的HIV-1（Ba-L株）的复制，EC 50值分别为1.2和3.7 nM。详细介绍了1 r及其相关化合物的合成和构效关系。
The search for new small-molecule CCR5 antagonists by high-throughput screening (HTS) of the Takeda chemical library using [I-125]RANTES and CHO/CCR5 cells led to the discovery of lead compounds (A, B) with a quaternary ammonium or phosphonium moiety, which were synthesized to investigate new MCP-1 receptor antagonists. A series of novel anilide derivatives 1 with a quaternary ammonium moiety were designed, synthesized, and tested for their CCR5 antagonistic activity. Through the optimization of lead compounds, we have found N,N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6, 7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]tetrahydro-2H-pyran-4-aminium chloride (1r, TAK-779) as a highly potent and selective nonpeptide CCR5 antagonist with a IC50 value of 1.4 nM in the binding assay. Compound Ir also inhibited the replication of macrophage (M)-tropic HIV-1 (Ba-L strain) in both MAGI-CCR5 cells and PBMCs with EC50 values of 1.2 and 3.7 nM, respectively. The synthesis and structure-activity relationships of 1r and its related compounds are detailed.