Fader Lee D, Carson Rebekah, Morin Sébastien, Bilodeau François, Chabot Catherine, Halmos Ted, Bailey Murray D, Kawai Stephen H, Coulombe René, Laplante Steven, Mekhssian Kevork, Jakalian Araz, Garneau Michel, Duan Jianmin, Mason Stephen W, Simoneau Bruno, Fenwick Craig, Tsantrizos Youla, Yoakim Christiane
Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
ACS Med Chem Lett. 2014 Apr 16;5(6):711-6. doi: 10.1021/ml500110j. eCollection 2014 Jun 12.
A scaffold replacement approach was used to identifying the pyridine series of noncatalytic site integrase inhibitors. These molecules bind with higher affinity to a tetrameric form compared to a dimeric form of integrase. Optimization of the C6 and C4 positions revealed that viruses harboring T124 or A124 amino acid substitutions are highly susceptible to these inhibitors, but viruses having the N124 amino acid substitution are about 100-fold less susceptible. Compound 20 had EC50 values <10 nM against viruses having T124 or A124 substitutions in IN and >800 nM in viruses having N124 substitions. Compound 20 had an excellent in vitro ADME profile and demonstrated reduced contribution of biliary excretion to in vivo clearance compared to BI 224436, the lead compound from the quinoline series of NCINIs.
采用支架置换方法来鉴定非催化位点整合酶抑制剂的吡啶系列。与整合酶的二聚体形式相比，这些分子与四聚体形式的亲和力更高。对C6和C4位置的优化表明，携带T124或A124氨基酸取代的病毒对这些抑制剂高度敏感，但具有N124氨基酸取代的病毒敏感性约低100倍。化合物20对整合酶中具有T124或A124取代的病毒的EC50值<10 nM，而对具有N124取代的病毒的EC50值>800 nM。与喹啉系列非催化位点整合酶抑制剂的先导化合物BI 224436相比，化合物20具有出色的体外药代动力学性质，并且显示出胆汁排泄对体内清除率的贡献降低。
