Romero D L, Olmsted R A, Poel T J, Morge R A, Biles C, Keiser B J, Kopta L A, Friis J M, Hosley J D, Stefanski K J, Wishka D G, Evans D B, Morris J, Stehle R G, Sharma S K, Yagi Y, Voorman R L, Adams W J, Tarpley W G, Thomas R C
DDR&D Pharmaceutics, Pharmacia & Upjohn, Inc, Kalamazoo, Michigan 49001, USA.
J Med Chem. 1996 Sep 13;39(19):3769-89. doi: 10.1021/jm960158n.
A novel class of bis(heteroaryl)piperazine (BHAP) analogs which possesses the ability to inhibit NNRTI (non-nucleoside reverse transcriptase inhibitor) resistant recombinant HIV-1 reverse transcriptase (RT) and NNRTI resistant variants of HIV-1 has been identified via targeted screening. Further investigation of the structure-activity relationships of close congeners of these novel (alkylamino)piperidine BHAPs (AAP-BHAPs) led to the synthesis of several compounds possessing the desired phenotype (e.g., activity against recombinant RTs carrying the Y181C and P236L substitutions). Further structural modifications were required to inhibit metabolism and modulate solubility in order to obtain compounds with the desired biological profile as well as appropriate pharmaceutical properties. The AAP-BHAPs with the most suitable characteristics were compounds 7, 15, and 36.
通过靶向筛选，已鉴定出一类新型的双（杂芳基）哌嗪（BHAP）类似物，其具有抑制对非核苷类逆转录酶抑制剂（NNRTI）耐药的重组HIV-1逆转录酶（RT）以及HIV-1的NNRTI耐药变体的能力。对这些新型（烷基氨基）哌啶BHAP（AAP-BHAP）的紧密同系物的构效关系进行进一步研究，导致合成了几种具有所需表型的化合物（例如，对携带Y181C和P236L取代的重组RT具有活性）。为了获得具有所需生物学特性以及适当药物性质的化合物，需要进行进一步的结构修饰以抑制代谢并调节溶解度。具有最合适特性的AAP-BHAP是化合物7、15和36。
