Development of β-amino alcohol derivatives that inhibit Toll-like receptor 4 mediated inflammatory response as potential antiseptics.
Development of β-amino alcohol derivatives that inhibit Toll-like receptor 4 mediated inflammatory response as potential antiseptics.
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DOI：
10.1021/jm2003365
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发表时间：
2011-07-14
影响因子：
7.3
通讯作者：
Yin, Hang
中科院分区：
文献类型：
--
作者：
Chavez, Sherry A.;Martinko, Alexander J.;Lau, Corinna;Pham, Michael N.;Cheng, Kui;Bevan, Douglas E.;Mollnes, Tom E.;Yin, Hang
Toll样受体4（TLR 4）诱导的促炎信号传导已直接涉及严重脓毒症并且代表有吸引力的治疗靶点。在此，我们报告了我们对抑制TLR 4信号通路的β-氨基醇衍生物的构效关系和初步的药物代谢/药代动力学研究。从体外细胞检查中鉴定了先导化合物，其对TLR 4信号传导的抑制作用具有μM效力，随后在离体全血模型中评估了其抑制TLR 4诱导的炎症反应的能力。此外，还评价了几种化合物的毒理学、特异性、溶解度、脑-血屏障渗透性和药物代谢。虽然还需要进一步优化，但我们的研究结果为这类小分子药物治疗严重脓毒症的未来药物开发奠定了基础。
Toll-like Receptor 4 (TLR4) induced pro-inflammatory signaling has been directly implicated in severe sepsis and represents an attractive therapeutic target. Herein, we report our investigations into the structure-activity relationship and preliminary drug metabolism/pharmacokinetics study of β-amino alcohol derivatives that inhibit the TLR4 signaling pathway. Lead compounds were identified from in vitro cellular examination with µM potency for their inhibitory effects on TLR4 signaling and subsequently assessed for their ability to suppress the TLR4-induced inflammatory response in an ex vivo whole blood model. In addition the toxicology, specificity, solubility, brain-blood barrier permeability, and drug metabolism of several compounds were evaluated. Although further optimizations are needed, our findings lay the groundwork for the future drug development of this class of small molecule agents for the treatment of severe sepsis.
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影响因子：
15
作者：
Jester, Benjamin W.;Cox, Kurt J.;Ghosh, Indraneel
通讯作者：
Ghosh, Indraneel
影响因子：
64.8
作者：
Park, Beom Seok;Song, Dong Hyun;Lee, Jie-Oh
通讯作者：
Lee, Jie-Oh
影响因子：
3.6
作者：
Matsunaga, Naoko;Tsuchimori, Noboru;Ii, Masayuki
通讯作者：
Ii, Masayuki
影响因子：
3.6
作者：
BEVINAKATTI, HS;BANERJI, AA
通讯作者：
BANERJI, AA
影响因子：
7.3
作者：
BUTERA, JA;SPINELLI, W;BAGLI, JF
通讯作者：
BAGLI, JF