Inhibition of amyloidogenesis by nonsteroidal anti-inflammatory drugs and their hybrid nitrates.
Inhibition of amyloidogenesis by nonsteroidal anti-inflammatory drugs and their hybrid nitrates.
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通过非甾体类抗炎药及其杂化硝酸盐抑制淀粉样蛋白发生。
DOI：
10.1021/jm101450p
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发表时间：
2011-04-14
影响因子：
7.3
通讯作者：
Thatcher, Gregory R. J.
中科院分区：
文献类型：
--
作者：
Schiefer, Isaac T.;Abdul-Hay, Samer;Wang, Huali;Vanni, Michael;Qin, Zhihui;Thatcher, Gregory R. J.
Poor blood-brain barrier penetration of non-steroidal anti-inflammatory drugs (NSAIDs) has been blamed for the failure of the selective amyloid lowering agent (SALA) R-flurbiprofen in phase 3 clinical trials for Alzheimer’s disease (AD). NO-donor NSAIDs (NO-NSAIDs) provide an alternative, gastric-sparing approach to NSAID SALAs, which may improve bioavailability. NSAID analogs were studied for anti-inflammatory activity and for SALA activity in N2a neuronal cells transfected with human amyloid precursor protein (APP). Flurbiprofen (1) analogs were obtained with enhanced anti-inflammatory and anti-amyloidogenic properties compared to 1, however, esterification led to elevated Aβ1–42 levels. Hybrid nitrate prodrugs possessed superior anti-inflammatory activity and reduced toxicity relative to the parent NSAIDs, including clinical candidate, CHF5074. Although hybrid nitrates elevated Aβ1–42 at higher concentration, SALA activity was observed at low concentrations (≤ 1 µM): both Aβ1–42 and the ratio of Aβ1–42/Aβ1–40 were lowered. This biphasic SALA activity was attributed to the intact nitrate drug. For several compounds the selective modulation of amyloidogenesis was tested using an immunoprecipitation MALDI-TOF approach. These data support the development of NO-NSAIDs as an alternative approach towards a clinically useful SALA.
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DOI：
10.1016/s0140-6736(20)32205-4
发表时间：
2021-04-24
期刊：
Lancet (London, England)
影响因子：
--
作者：
Scheltens P;De Strooper B;Kivipelto M;Holstege H;Chételat G;Teunissen CE;Cummings J;van der Flier WM
通讯作者：
van der Flier WM
影响因子：
4
作者：
Imbimbo, Bruno P.;Giardino, Luciana;Calza, Laura
通讯作者：
Calza, Laura
影响因子：
82.9
作者：
Kukar, T;Murphy, MP;Golde, TE
通讯作者：
Golde, TE
影响因子：
158.5
作者：
in 't Veld, BA;Ruitenberg, A;Stricker, BHC
通讯作者：
Stricker, BHC
影响因子：
3.6
作者：
Kotoris, CC;Chen, MJ;Taylor, SD
通讯作者：
Taylor, SD