ISOXAZOLES IN MEDICINAL CHEMISTRY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 特权结构是指某些分子支架似乎能够与多个受体靶点结合，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有几种作用：前药、生物同工酶、间隔基，以及几个含有异恶唑的药物在一般医学实践中的例子。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。我们在假说驱动的基于结构的药物设计方面取得的最令人鼓舞的进展是：(1)用于治疗神经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)针对c-myc癌基因中G-4DNA构象的抗癌药物。在AMPA(氨甲基异恶唑丙酸)及其类似物的情况下，异沙唑提供构象限制，它们是谷氨酸受体配体，已被证明在确定这一重要神经递质的亚型特异性方面具有重要作用。我们已经开发出了我们认为是第一个催化不对称合成AMPA类似物的方法，并发现了GluR2受体和XC-转运蛋白系统之间的结构-活性关系(结构-活性关系)。在我们对4-异恶唑-1，4-二氢吡啶(ID)钙通道阻滞剂的研究中，异恶唑起到了生物同工酶的作用，其中我们观察到了强劲的钙通道活性(个位数纳米分子)以及明显的对映选择性作用。我们已经发现了ID的独特的SAR，并开发了一个药物受体模型作为一个工作假说。我们最新的合成研究集中在荧光团与ID支架的共价结合上，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，并在三维空间中精确地排列它们。在美国国家癌症研究所的筛查方案中，NSC 694332被发现对十几种肿瘤细胞株表现出个位数的微摩尔抑制作用，并被国家癌症研究所的生物评估委员会选中进行体内筛查。我们提出了一个可行的假设，即G-4DNA代表分子靶点，并获得了支持这一假设的证据。我们正在将实验室中的合成方法应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.¿