ISOXAZOLES IN MEDICINAL CHEMISTRY

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，不一定是研究者的机构。 术语特权结构是指某些分子支架似乎能够结合多种受体靶标，因此经过适当的结构修饰，可以表现出多种活性。异恶唑环在药物化学中起几种作用：前药、生物电子等排体、间隔基，并且含有异恶唑的药物的几个实例在一般医学实践中。我们正在开发合成方法，将异恶唑支架应用于药物化学中的重大问题。我们在基于假设驱动的基于结构的药物设计方面取得了最令人鼓舞的进展，包括（1）用于治疗神经系统疾病的神经递质类似物，（2）硝苯地平类抗高血压钙通道拮抗剂的SAR，以及（3）靶向c-myc癌基因中G-4 DNA构象的抗癌药物。在AMPA？（氨基甲基异恶唑丙酸）及其类似物的情况下，异恶唑提供构象限制，AMPA？（氨基甲基异恶唑丙酸）及其类似物是谷氨酸受体配体，其已被证明在定义这种重要神经递质的亚型特异性方面是重要的。我们已经开发了我们认为是AMPA类似物的第一个催化不对称合成，并发现了GluR 2受体和系统XC-转运蛋白之间的SAR（结构活性关系）区别。异恶唑在我们的4-异恶唑基-1，4-二氢吡啶<$（ID）钙通道阻断剂研究中作为生物电子等排体发挥作用，其中我们观察到了稳健的钙通道活性（个位数纳摩尔）以及明显的对映体选择性作用。我们已经发现了一个独特的SAR的ID，并已制定了一个药物受体模型作为工作假设。我们最近的合成研究集中在荧光团与ID支架的共价连接上，以研究钙通道的结构动力学。我们实验室开发的一类新化合物，以NCS 694332为例，使用异恶唑作为连接DNA相互作用基团的关键，并将它们排列成三维精确构象。NSC 694332在国家癌症研究所（NCI）的筛选方案中被发现对十几种肿瘤细胞系表现出单位数微摩尔抑制，并被NCI的生物评价委员会选择用于体内筛选。我们已经提出了一个工作假设，即G-4 DNA代表分子靶点，并获得了支持这一假设的证据。我们正在申请我们的实验室将合成方法用于其他药物发现工作，并在2型糖尿病和传染病领域取得了初步进展。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The term privileged structure refers to certain molecular scaffolds that appear to be capable of binding to multiple receptor targets, and consequently with appropriate structure modifications, could exhibit multiple activities. The isoxazole ring plays several roles in medicinal chemistry: prodrug, bioisostere, spacer, and several examples of isoxazole containing drugs are in general medical practice. We are developing synthetic methodology to apply the isoxazole scaffold to significant problems in medicinal chemistry. Our most encouraging progress in our hypothesis-driven Structure-based drug design has been made in (1) neurotransmitter analogs for the treatment for neurological disorders, (2) the SAR of Anti-hypertensive calcium channel antagonists of the nifedipine class, and (3) anti-cancer agents that target G-4 DNA conformation in the c-myc oncogene. Isoxazoles provide conformational restriction in the case of AMPA¿ (Amino Methyl isoxazole Propionic Acid) and its analogs, which are glutamate receptor ligands which have proved important in defining sub-type specificity of this important neurotransmitter. We have developed what we believe to be the first catalytic asymmetric synthesis of AMPA analogs, and have discovered an SAR (Structure Activity Relationship)¿ distinction between the GluR2 receptor and System XC- transporter.¿ The isoxazole serves a function as a bioisostere in our studies of 4-isoxazolyl-1,4-dihydropyridine¿ (ID) calcium channel blockers, wherein we have observed both robust calcium channel activity (single digit nanomolar), as well as a pronounced enantioselectivity of action. We have uncovered a unique SAR for the IDs, and have developed a drug-receptor model as a working hypothesis. Our most recent synthetic studies have focused on the covalent attachment of fluorophores to the ID scaffold, to study the structural dynamics of the calcium channel.¿ A new class of compounds developed in our lab, exemplified by NCS 694332, use the isoxazole as a linchpin to both connect DNA interactive groups and arrange them in a precise conformation in three dimensions. NSC 694332 was found to exhibit single digit micromolar inhibition of a dozen tumor cell lines in the National Cancer Institute's (NCI) screening protocol, and selected by the NCI's Biological Evaluation Committee for in vivo screening. We have developed a working hypothesis that G-4 DNA represents the molecular target, and have obtained evidence supporting that hypothesis. We are applying¿synthetic methodology in our labs to other drug discovery endeavors, and have made preliminary progress in the Type 2 diabetes and infectious disease arenas.¿