STABLE STEREOISOMER ANALOGS OF TOPO IIBETA INHIBITORS

TOPO IIBETA 抑制剂的稳定立体异构体类似物

• 批准号: 6298527
• 负责人: RALPH E PARCHMENT
• 金额: $ 13.95万
• 依托单位: SCITECH DEVELOPMENT, LLC
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6298527
• 关键词: DNA gyrase; analog; antineoplastics; breast neoplasms; chemical stability; chemical synthesis; colon neoplasms; drug design /synthesis /production; drug metabolism; enzyme inhibitors; neoplasm /cancer pharmacology; prostate neoplasms; stereoisomer

SciTech Development LLC optimizes lead anticancer agents via novel, rational modifications that enhance drug performance in vivo. 2-Aryl- lactic acids show highly selective activity against solid tumors and novel, specific inhibition of topoisomerase II-beta. Their stereochemistry reportedly affects therapeutic index and drug disposition, attracting SciTech's interest. At AACR-NCI-EORTC 1999, a poster showed rodents, dogs, and primates rapidly converting the S stereoisomer of a NCI clinical candidate into R In vitro, bone marrow neutrophil progenitors tolerated the S isomer better than R. Hence, the goal of this SBIR: development of novel S isomers of 2-aryl-lactic acids refractory to stereoinversion in vivo and thereby better anticancer agents. SciTech proposes three chemical synthetic strategies for stabilizing 2(S)-aryl-lactic acid anticancer agents. Phase I will demonstrate feasibility and assess prototype structures using in vitro tests for human metabolism, human bone marrow safety, and solid tumor efficacy. In Phase II, analogs will be synthesized using these strategies, required to pass this in vitro testing and in vivo testing for stabilized stereochemistry, and clinical candidates prioritized by efficacy in human tumor xenograft models. This research could lead to effective solid tumor agents and also enhance the drug being developed by the NCI. PROPOSED COMMERCIAL APPLICATIONS: 2-Aryl-lactic acid anticancer agents are highly active against a broad panel of solid tumors in preclinical models including tumors that represent major market opportunities for highly active drugs: cancers of the breast, colon, prostate, and pancreas. The proposed structures stabilize the most active stereoisomers and create novel compounds not covered by existing patents in this area.

SciTech Development LLC通过新型、合理的修饰来优化主要抗癌药物，以增强药物在体内的性能。2-芳基-乳酸显示出对实体瘤的高度选择性活性和拓扑异构酶II-β的新的特异性抑制。据报道，它们的立体化学影响治疗指数和药物处置，吸引了SciTech的兴趣。在1999年的AACR-NCI-EORTC上，一张海报显示啮齿动物、犬和灵长类动物将NCI临床候选药物的S立体异构体快速转化为R。在体外，骨髓中性粒细胞祖细胞对S异构体的耐受性优于R。因此，该SBIR的目标是：开发体内难以立体转化的2-芳基乳酸的新型S异构体，从而开发更好的抗癌药物。SciTech提出了三种稳定2（S）-芳基-乳酸抗癌剂的化学合成策略。第一阶段将证明可行性，并使用人体代谢，人骨髓安全性和实体瘤疗效的体外试验评估原型结构。在II期，将使用这些策略合成类似物，需要通过该体外测试和体内测试以获得稳定的立体化学，并且临床候选物通过在人肿瘤异种移植模型中的功效进行优先级排序。这项研究可能会导致有效的实体瘤药物，也会增强NCI正在开发的药物。拟议的商业应用：2-芳基-乳酸抗癌剂在临床前模型中对广泛的实体瘤具有高度活性，包括代表高活性药物主要市场机会的肿瘤：乳腺癌、结肠癌、前列腺癌和胰腺癌。拟议的结构稳定了最具活性的立体异构体，并创造了该领域现有专利未涵盖的新型化合物。