Tacrines as Therapeutic Agents for Alzheimer's Disease. IV. The Tacripyrines and Related Annulated Tacrines

Bartolini Manuela; Marco‐Contelles José

摘要

Abstract > Notwithstanding the clinical use of tacrine was hampered by severe hepatotoxicity, tacrine still remains a reference scaffold in the search for new efficient drugs for Alzheimer's disease therapy. In this account we summarize the efforts toward the development and characterization of non‐hepatotoxic tacripyrines and related tacrine analogues resulting from the substitution of the benzene ring by a 1,4‐dihydropyridine, a 1,2,3,4‐tetrahydropyrimidine or a pyridone nucleus. These efforts have successfully led to the identification of a number of promising hits endowed with interesting multifunctional profiles. These include the 4′‐metoxytacripyrine ( S )‐ ITH122 , able to target cholinesterases (ChEs), beta‐amyloid (A β ) and Ca 2+ channels, the racemic 3′‐methoxytacripyrimidine EB65F2 , the first fully balanced micromolar inhibitor of ChEs and Ca 2+ channels, and tacripyrine (?)‐SCR1693 a GSK‐3β (enzyme involved in tau phosphorylation) inhibitor able to also lower A β production in N2a cells. </abstract> </span> <span class="z_kbtn z_kbtnclass hoverxs" style="display: none;">展开▼</span> </div> <div class="translation abstracttxt"> <span class="zhankaihshouqi fivelineshidden" id="abstract"> <span>机译：</span><Abstract Type =“Main”XML：Lang =“en”> <标题类型=“main”>摘要</ title> >尽管临床使用Tacrine被严重的肝毒性受到阻碍，但Tacrine仍然是参考脚手架寻找阿尔茨海默病治疗的新高效药物。在本次账户中，我们总结了由1,4-二氢吡啶，1,2,3,4-四氢嘧啶或吡啶酮取代苯环的非肝毒性毒素和相关的酮毒素类似物的开发和表征。核。这些努力已成功地导致识别许多有很多有趣的多功能型材的令人兴奋的命中。这些包括能够靶向胆碱酯酶（Ches），β-淀粉样蛋白（A>β</ I>）和Ca 2 + </ sup>通道，外消旋3'-甲氧基丙酮嘧啶 eb65f2 <ches和ca 2 + </ sup>通道的第一个完全平衡的微胆抑制剂，以及甲丙吡嗪<B>（？） - SCR1693 </ b>在N2A细胞中抑制剂的GSK-3β（参与TAU磷酸化的酶）抑制剂。 </ p> </ abstract> </span> <span class="z_kbtn z_kbtnclass hoverxs" style="display: none;">展开▼</span> </div> </div> <div class="record"> <h2 class="all_title" id="enpatent33" >著录项</h2> <ul> <li> <span class="lefttit">来源</span> <div style="width: 86%;vertical-align: text-top;display: inline-block;"> <a href='/journal-foreign-16132/'>《Chemical record》</a> <b style="margin: 0 2px;">|</b><span>2019年第5期</span><b style="margin: 0 2px;">|</b><span>共11页</span> </div> </li> <li> <div class="author"> <span class="lefttit">作者</span> <p id="fAuthorthree" class="threelineshidden zhankaihshouqi"> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Bartolini Manuela&option=202" target="_blank" rel="nofollow">Bartolini Manuela;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Marco‐Contelles José&option=202" target="_blank" rel="nofollow">Marco‐Contelles José;</a> </p> <span class="z_kbtnclass z_kbtnclassall hoverxs" id="zkzz" style="display: none;">展开▼</span> </div> </li> <li> <div style="display: flex;"> <span class="lefttit">作者单位</span> <div style="position: relative;margin-left: 3px;max-width: 639px;"> <div class="threelineshidden zhankaihshouqi" id="fOrgthree"> <p>Department of Pharmacy and BiotechnologyAlma Mater Studiorum University of BolognaVia Belmeloro 6 40126 Bologna Italy;</p> <p>Laboratory of Medicinal Chemistry (IQOG CSIC)3 Juan de la Cierva 28006 Madrid Spain;</p> </div> <span class="z_kbtnclass z_kbtnclassall hoverxs" id="zhdw" style="display: none;">展开▼</span> </div> </div> </li> <li > <span class="lefttit">收录信息</span> <span style="width: 86%;vertical-align: text-top;display: inline-block;"></span> </li> <li> <span class="lefttit">原文格式</span> <span>PDF</span> </li> <li> <span class="lefttit">正文语种</span> <span>eng</span> </li> <li> <span class="lefttit">中图分类</span> <span><a href="https://www.zhangqiaokeyan.com/clc/159.html" title="化学">化学;</a></span> </li> <li class="antistop"> <span class="lefttit">关键词</span> <p style="width: 86%;vertical-align: text-top;"> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Multitarget small molecules&option=203" rel="nofollow">Multitarget small molecules;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Tacripyrines&option=203" rel="nofollow">Tacripyrines;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Tacripyrimedones&option=203" rel="nofollow">Tacripyrimedones;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Tacripyrimidines&option=203" rel="nofollow">Tacripyrimidines;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Hupertacrines&option=203" rel="nofollow">Hupertacrines;</a> </p> <div class="translation"> 机译：多元小分子;甲丙啶;甲丙酮蛋黄酱;甲丙吡啶胺;Hupertacrines; </div> </li> </ul> </div> </div> <div class="literature cardcommon"> <div class="similarity "> <h3 class="all_title" id="enpatent66">相似文献</h3> <div class="similaritytab clearfix"> <ul> <li class="active" >外文文献</li> <li >中文文献</li> <li >专利</li> </ul> </div> <div class="similarity_details"> <ul > <li> <div> <b>1. </b><a class="enjiyixqcontent" href="/journal-foreign-detail/0704022080048.html">Tacrines as Therapeutic Agents for Alzheimer's Disease. IV. The Tacripyrines and Related Annulated Tacrines</a> <b>[J]</b> . <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Bartolini Manuela&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Bartolini Manuela,</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Marco‐Contelles José&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Marco‐Contelles José </a> <a href="/journal-foreign-16132/" target="_blank" rel="nofollow" class="tuijian_authcolor">Chemical record .</a> <span>2019</span><span>,第5期</span> </span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：种子作为阿尔茨海默病的疗养药物。 IV。 TaCri吡啶和相关的子弹</span> </p> </li> <li> <div> <b>2. </b><a class="enjiyixqcontent" href="/journal-foreign-detail/0704013791216.html">Molecular perception of interactions between bis(7)tacrine and cystamine-tacrine dimer with cholinesterases as the promising proposed agents for the treatment of Alzheimer's disease</a> <b>[J]</b> . <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Eslami Mahboobeh&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Eslami Mahboobeh,</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Hashemianzadeh Seyed Majid&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Hashemianzadeh Seyed Majid,</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Bagherzadeh Kowsar&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Bagherzadeh Kowsar,</a> <a href="/journal-foreign-33806/" target="_blank" rel="nofollow" class="tuijian_authcolor">Journal of Biomolecular Structure and Dynamics .</a> <span>2016</span><span>,第3a4期</span> </span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：bis（7）他克林与胱胺酯-他克林二聚体与胆碱酯酶之间相互作用的分子感知，可作为拟议的治疗阿尔茨海默氏病的药物</span> </p> </li> <li> <div> <b>3. </b><a class="enjiyixqcontent" href="/journal-foreign-detail/0704014701349.html">Tacripyrines, the First Tacrine-Dihydropyridine Hybrids, as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease</a> <b>[J]</b> . <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Marco-Contelles J&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Marco-Contelles J,</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Leon R&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Leon R,</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=de los Rios C&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">de los Rios C,</a> <a href="/journal-foreign-35108/" target="_blank" rel="nofollow" class="tuijian_authcolor">Journal of Medicinal Chemistry .</a> <span>2009</span><span>,第9期</span> </span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：Tacripyrines，第一个Tacrine-Dihydropyridine杂种，作为多靶点定向配体，用于治疗阿尔茨海默氏病</span> </p> </li> <li> <div> <b>4. </b><a class="enjiyixqcontent" href="/academic-conference-foreign_advances-in-human-vector-control_thesis/020511808485.html">Chapter 10 Pharmacological Mapping of the Acetylcholinesterase Catalytic Gorge in Mosquitoes with Bis(n)-Tacrines</a> <b>[C]</b> . <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Troy D. 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Process for obtaining them</a> <b>[P]</b> . <span> 外国专利：  ES2144353A1 </span> <span> . 2000-06-01</span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：新型他克林类似物：阿尔茨海默氏症和帕金森氏病患者的潜在神经保护剂。获得它们的过程 </span> </p> </li> <li> <div> <b>5. </b><a class="enjiyixqcontent" href="/patent-detail/06130420286159.html">THERAPEUTIC AGENT AND PREVENTATIVE AGENT FOR ALZHEIMER'S DISEASE.</a> <b>[P]</b> . <span> 外国专利：  MX2012012410A </span> <span> . 2012-12-17</span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：老年痴呆症的治疗剂和预防剂。 </span> </p> </li> </ul> </div> </div> </div> <div class="theme cardcommon" style="overflow: auto;display:none"> <h3 class="all_title" id="enpatent55">相关主题</h3> <ul id="subject"> </ul> </div> </div> </div> </div> <div class="right rightcon"> <div class="details_img cardcommon clearfix" style="margin-bottom: 10px;display:none;" > </div> </div> </div> <div id="thesis_get_original1" class="downloadBth" style="bottom: 19px;z-index: 999;" onclick="ywcd('0704022080048','4',7,2,1,'',this,24)" class="delivery" prompt="010401" title="通过人工服务将文献原文发送至邮箱" >获取原文</div> <div class="journalsub-pop-up" style="display: none"> <div class="journal-sub"> <h2>期刊订阅</h2> <img src="https://cdn.zhangqiaokeyan.com/img/loginclose.png" alt="关闭" onclick="$('.journalsub-pop-up').hide()"> <p class="pardon">抱歉，该期刊暂不可订阅，敬请期待！</p> <p class="current">目前支持订阅全部北京大学中文核心（2020）期刊目录。</p> <div style="display: flex;margin-top: 69px;justify-content: space-between;"> <div class="no-sub" onclick="$('.journalsub-pop-up').hide()">暂不订阅</div> <div class="other-sub" onclick="continueSub('from=pc-detail')">继续订阅其他期刊</div> </div> </div> </div> <div class="right_btn"> <ul> <li class="gouwuche">  </li> <li class="yijian"> <a href="javascript:void(0);" onclick="link_analysis('/mycenter/auth/complaint.html',this)" title="意见反馈">意见反馈</a> </li> <li class="top"> <a href="javascript:scrollTo(0,0);" title="回到顶部">回到顶部</a> </li> <li class="shouye"> <a href="/" title="首页">回到首页</a> </li> </ul> </div> <div class="xllindexfooter"> <div class="xllindexfootercenter"> <div class="xllindexfooterleft left" > <div class="xllindexfooterleftli"> <ul> <li><a href="/about.html" title="关于掌桥">关于掌桥</a></li> <li><a href="/help/helpmap.html" title="资源导航">资源导航</a></li> <li><a href="/help/helpguide.html" title="新手指南">新手指南</a></li> <li><a href="/help/helpcenter.html" title="常见问题">常见问题</a></li> <li><a href="/sitemap.html" title="网站地图">网站地图</a></li> <li><a href="/help/helpcenter.html?type=9" title="版权声明">版权声明</a></li> </ul> </div> <div class="xllindexfooterleft"> <p class="xllindexfooterlefteamil">客服邮箱：kefu@zhangqiaokeyan.com</p> <div class="xllindexfooterlefttcp"> <div class="xllindexfooterpoliceiimg"></div> <div class="xllindexfooterpoliceispan"> <span>京公网安备：11010802029741号 </span> <span>ICP备案号：<a href="https://beian.miit.gov.cn" rel="nofollow" target="_blank" title="ICP备案号">京ICP备15016152号-6</a></span> <span>六维联合信息科技 (北京) 有限公司©版权所有</span> </div> </div> </div> </div> <div class="xllindexfooterright left"> <ul> <li> <p style="font-weight: bold;">客服微信</p> <div></div> </li> <li> <p style="font-weight: bold;">服务号</p> <div></div> </li> </ul> </div> </div> </div> <span id="0704022080048down" data-source="7," data-out-id="oj2K972TjJVmBXFtj/HvwO/PKZJkkKmx3hgIK5nEGSIqfq7slStWp7SRWrInTSco," data-f-source-id="7" data-title="Tacrines as Therapeutic Agents for Alzheimer's Disease. 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