Identification of SQ609 as a lead compound from a library of dipiperidines.
Identification of SQ609 as a lead compound from a library of dipiperidines.
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DOI：
10.1016/j.bmcl.2011.07.015
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发表时间：
2011-09-15
影响因子：
2.7
通讯作者：
Protopopova, Marina
中科院分区：
文献类型：
--
作者：
Bogatcheva, Elena;Hanrahan, Colleen;Nikonenko, Boris;de los Santos, Gladys;Reddy, Venkata;Chen, Ping;Barbosa, Francis;Einck, Leo;Nacy, Carol;Protopopova, Marina
我们最近报道，围绕二哌啶支架创建的化合物表现出抗结核分枝杆菌 (Mtb) 的活性（Bogatcheva, E.；Hanrahan, C.；Chen, P.；Gearhart, J.；Sacksteder, K.；Einck, L.；Nacy, C.；Protopopova, M. Bioorg. Med. Chem. Lett.2010, 20, 201）。为了优化二哌啶化合物系列并选择先导化合物进入临床前研究，我们评估了我们专有库的构效关系 (SAR)。 (哌啶-4-基甲基)哌啶支架是抗菌活性所需的重要结构元件。基于 SAR，我们合成了一个包含 313 个新二哌啶的重点库，以描述负责抗结核活性的其他结构特征。鉴定出 30 种新的活性化合物，其对 Mtb 的 MIC 为 10-20μg/ml，但没有一个比该系列的原始化合物 SQ609、SQ614 和 SQ615 更好。在体外Mtb感染的巨噬细胞中，SQ609和SQ614在4μg/ml时抑制90%以上的细胞内细菌生长； SQ615 对这些细胞有毒。在感染 Mtb 的小鼠中，SQ609 完全阻止了体重减轻，但 SQ614 则不然，并且 SQ609 具有延长的治疗效果，在停止治疗后可延长 10-15 天。根据体外和体内抗结核活性，SQ609 被确定为该系列中同类最佳的二哌啶化合物。
We recently reported that compounds created around a dipiperidine scaffold demonstrated activity against Mycobacterium tuberculosis (Mtb) (Bogatcheva, E.; Hanrahan, C.; Chen, P.; Gearhart, J.; Sacksteder, K.; Einck, L.; Nacy, C.; Protopopova, M. Bioorg. Med. Chem. Lett.2010, 20, 201). To optimize the dipiperidine compound series and to select a lead compound to advance into preclinical studies, we evaluated the structure-activity relationship (SAR) of our proprietary libraries. The (piperidin-4-ylmethyl)piperidine scaffold was an essential structural element required for antibacterial activity. Based on SAR, we synthesized a focused library of 313 new dipiperidines to delineate additional structural features responsible for antitubercular activity. Thirty new active compounds with MIC 10-20μg/ml on Mtb were identified, but none was better than the original hits of this series, SQ609, SQ614, and SQ615. In Mtb-infected macrophages in vitro, SQ609 and SQ614 inhibited more than 90% of intracellular bacterial growth at 4μg/ml; SQ615 was toxic to these cells. In mice infected with Mtb, weight loss was completely prevented by SQ609, but not SQ614, and SQ609 had a prolonged therapeutic effect, extended by 10-15days, after cessation of therapy. Based on in vitro and in vivo antitubercular activity, SQ609 was identified as the best-in-class dipiperidine compound in the series.
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DOI：
10.1073/pnas.96.22.12833
发表时间：
1999-10-26
影响因子：
11.1
作者：
Wilson, W;DeRisi, J;Schoolnik, GK
通讯作者：
Schoolnik, GK
影响因子：
7.3
作者：
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通讯作者：
Kozikowski, Alan P.
影响因子：
--
作者：
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通讯作者：
Barry, CE
影响因子：
3.9
作者：
Tomioka, Haruaki;Tatano, Yutaka;Shimizu, Toshiaki
通讯作者：
Shimizu, Toshiaki
影响因子：
3.5
作者：
Tripathi, R. P.;Saxena, Nisha;Sinha, S.
通讯作者：
Sinha, S.