Synthesis and bioactivity of novel bis(heteroaryl)piperazine (BHAP) reverse transcriptase inhibitors: structure-activity relationships and increased metabolic stability of novel substituted pyridine analogs.
Synthesis and bioactivity of novel bis(heteroaryl)piperazine (BHAP) reverse transcriptase inhibitors: structure-activity relationships and increased metabolic stability of novel substituted pyridine analogs.
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DOI：
10.1021/jm960269m
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发表时间：
1996-12
影响因子：
7.3
通讯作者：
M. Genin;T. Poel;Y. Yagi;C. Biles;I. Althaus;B. Keiser;L. Kopta;J. M. Friis;F. Reusser;W. Adams;R. Olmsted;R. Voorman;R. Thomas;D. Romero
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文献类型：
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作者：
M. Genin;T. Poel;Y. Yagi;C. Biles;I. Althaus;B. Keiser;L. Kopta;J. M. Friis;F. Reusser;W. Adams;R. Olmsted;R. Voorman;R. Thomas;D. Romero
双(杂芳基)哌嗪(BHAP)类逆转录酶抑制剂(RTI)的主要代谢途径是吡啶环上3-乙基或3-异丙氨基的氧化N-脱烷基。这一代谢途径也是(烷氨基)哌啶BHAP类似物(AAP-BHAP)的主要代谢模式，其中4-(烷氨基)哌啶取代了BHAP的哌嗪环。新型AAP-BHAP具有抑制非核苷类逆转录酶抑制物(NNRTI)抗性的重组HIV-1RT和抗NNRTI的HIV-1变异株的能力。本报告描述了一种防止这种降解的方法，包括用3-叔丁基氨基或3-烷氧基取代3-乙基或3-异丙基氨基。介绍了这些类似物的合成、生物活性和代谢稳定性。大多数类似物在酶和细胞培养试验中保持抑制活性。一般来说，吡啶环上的3-乙氧基或3-异丙氧基取代基，如化合物10、20或21，可提高稳定性。3-叔丁胺取代基在AAP-BHAP系列类似物中有一定的益处，但在BHAP系列中没有显著影响。最后，吲哚取代的性质有时对代谢稳定性起着重要作用，特别是在BHAP系列类似物中。
The major route of metabolism of the bis(heteroaryl)piperazine (BHAP) class of reverse transcriptase inhibitors (RTIs), atevirdine and delavirdine, is via oxidative N-dealkylation of the 3-ethyl- or 3-isopropylamino substituent on the pyridine ring. This metabolic pathway is also the predominant mode of metabolism of (alkylamino)piperidine BHAP analogs (AAP-BHAPs), compounds wherein a 4-(alkylamino)piperidine replaces the piperazine ring of the BHAPs. The novel AAP-BHAPs possess the ability to inhibit non-nucleoside reverse transcriptase inhibitor (NNRTI) resistant recombinant HIV-1 RT and NNRTI resistant variants of HIV-1. This report describes an approach to preventing this degradation which involves the replacement of the 3-ethyl- or 3-isopropylamino substituent with either a 3-tert-butylamino substituent or a 3-alkoxy substituent. The synthesis, bioactivity and metabolic stability of these analogs is described. The majority of analogs retain inhibitory activities in enzyme and cell culture assays. In general, a 3-ethoxy or 3-isopropoxy substituent on the pyridine ring, as in compounds 10, 20, or 21, resulted in enhanced stabilities. The 3-tert-butylamino substituent was somewhat beneficial in the AAP-BHAP series of analogs, but did not exert a significant effect in the BHAP series. Lastly, the nature of the indole substitution sometimes plays a significant role in metabolic stability, particularly in the BHAP series of analogs.