Novel Aminoadamantane Nitrates for the Treatment of Neurological Diseases

 描述(申请人提供)：美金刚是一种氨基金刚烷，在美国和欧洲被批准用于治疗中到重度阿尔茨海默病。美金刚选择性地抑制异常活跃的N-甲基-D-天冬氨酸型谷氨酸受体(NMDAR)通道，同时保留正常的谷氨酸活性和生理神经元功能(Lipton，2006；Lipton，2007a，b)。N端或胞外区的半胱氨酸残基的S亚硝化进一步下调了病理性N-甲基-D-天冬氨酸受体的活性。利用这些洞察力，我们开发了一系列双功能拮抗剂，硝基安非他明，不仅优先结合到开放通道状态，而且利用美金刚药效基团作为归巢基序，选择性地将NO靶向第二个调控位点。我们的数据表明，其中一些美金胺类似物具有良好的效力，同时保持了对持续开放的NMDAR通道的选择性。最重要的是，在体外和体内动物模型中，它们似乎比美金刚具有更强的神经保护特性。我们的结果提供了结构性指导，以进一步优化，然后确定具有最佳配置文件的潜在开发候选，以最大限度地发挥神经保护作用。PRI拥有，而PI是最初的硝基美金胺专利的共同发明人(Wang，2002,2003,2008)。我们的合作者(也是共同发明人)斯图尔特·利普顿教授的实验室最近的研究表明，我们的一种硝基金刚烷(YQW-036，1-氨基-3，5-二乙基-7-硝酸金刚烷)在拯救/保护突触方面比美金刚具有独特的优势(Talantova，2013)。这种化合物优先和独特地调节致病的突触外NMDAR而不是突触NMDAR。第一阶段寻求根据我们前景看好的双靶标先导化合物确定开发候选者。第二阶段将支持支持IND的翻译研究。这一里程碑的实现将产生一种治疗阿尔茨海默病的专利一流的疾病修改药物。

 DESCRIPTION (provided by applicant): Memantine, an aminoadamantane, is approved to treat moderate-to-severe Alzheimer's disease in the US and Europe. Memantine selectively inhibits abnormally active N-methyl-D-aspartate-type glutamate receptor (NMDAR) channels, while preserving normal glutamate activity and physiological neuronal function (Lipton, 2006; Lipton, 2007a,b). Pathological NMDA receptor activity is further down-regulated by S-nitrosylation of cysteine residues located on the N-terminus or extracellular domain. Taking advantage of these insights, we have developed a series of bifunctional antagonists, nitromemantines, that not only preferentially bind to the open-channel state but also selectively target NO to a second modulatory site using the memantine pharmacophore as a homing motif. Our data suggest that some of these memantine analogs have good potency, while maintaining selectivity for persistently open NMDAR channels. Most importantly, they appear to have greater neuroprotective properties than memantine in both in vitro and in vivo animal models. Our results provide structural guidance to further optimize, and then identify, a potential development candidate with an optimal profile to maximize neuroprotective effects. PRI owns, and the PI is a co-inventor on the original nitromemantine patents (Wang, 2002, 2003, 2008). Recent work from the laboratory of our collaborator (and co-inventor), Prof. Stuart Lipton, demonstrates the unique superiority of one of our nitromemantines (YQW- 036, 1-amino-3,5-diethyl-7-nitrateadamantane) versus memantine to rescue/protect synapses (Talantova, 2013). This compound preferentially and uniquely modulates pathogenic extrasynaptic NMDARs versus synaptic NMDARs. Phase I seeks to identify a development candidate based on our promising dual-targeted lead compound. Phase II will support translational, IND-enabling studies. The achievement of this milestone will generate a proprietary first-in-class, disease-modifying drug for Alzheimer's disease.