Improving Metabolic Stability Profiles in Kinase Inhibitor Development Through the Use of 1-Aminonorbornanes as Aniline Bioisosteres

通过使用 1-氨基降冰片烷作为苯胺生物等排体改善激酶抑制剂开发中的代谢稳定性

• 批准号: 10348159
• 负责人: James Lester Collins
• 金额: $ 1.18万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2022-05-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10348159
• 关键词: Address; Affinity; Aniline; Antineoplastic Agents; Behavior; Binding; Biological; Characteristics; Chemicals; Chemotherapy-Oncologic Procedure; Clinical; Collaborations; Dangerousness; Degradation Pathway; Development; Drug Industry; Drug Interactions; Engineering; Erlotinib; Event; FDA approved; Hepatotoxicity; Individual; Lead; Literature; Malignant Neoplasms; Metabolic; Metabolism; Michigan; Oncolytic; Organic Chemistry; Oxides; Pharmaceutical Preparations; Pharmacologic Substance; Photochemistry; Positioning Attribute; Property; Publishing; Risk; Structure; System; Therapeutic; Time; Toxic effect; Tyrosine Kinase Inhibitor; Universities; Work; analog; base; design; drug candidate; drug development; drug induced liver injury; drug metabolism; functional group; improved; kinase inhibitor; lapatinib; next generation; novel; oxidation; scaffold; stem; translational impact

Improving Metabolic Stability Profiles in Kinase Inhibitor Development Through the Use of 1- Aminonorbornanes as Aniline Bioisosteres Abstract The proposed work focuses on the development of 1-aminonorbornanes and demonstration that these systems can serve as metabolically-inert aniline bioisosteres. Toxicity profiles, particularly hepatotoxicity, requiring black box warnings are common among FDA-approved tyrosine kinase inhibitors. Anilines, although they are commonly used in the pharmaceutical industry, are often easily oxidized by CYP450s. Formation of reactive intermediates upon oxidation often times leads to adverse drug-drug interactions and idiosyncratic toxicities. Unfortunately, there are currently no clear isosteres for anilines, forcing medicinal chemists to continually use these motifs despite the known proclivity to metabolism-derived off-target toxicity. A photochemical strategy to readily synthesize 1-aminonorbornanes has been developed and published. Preliminary results suggest the 1- aminonorbornane motifs occupy similar chemical space to anilines, despite their drastic structural difference. These results have served as the initial proof-of-concept that the saturated carbocyclic framework of 1- aminonorboranes can serve as a reliable aniline bioisostere. This preliminary evidence has optimally-positioned this project to implement our synthetic designs and discoveries into disruptive translational advances. This will be accomplished through the development of novel 1-aminonorbornane-based analogs of the oncolytic kinase inhibitors, lapatinib and erlotinib. These isosteric analogs are anticipated to offer analogous anti-neoplastic efficacy while avoiding the adverse metabolic events that have limited the utility of these and other cancer chemotherapies. This work will thus validate the utility of 1-aminonorbornanes as aniline bioisosteres and provide the momentum necessary to shift the drug development paradigm from risk-laden aromatic motifs to better- tolerated, saturated building blocks.

通过使用1- Aminonorbornanes作为苯胺生物膜蛋白酶 抽象的 拟议的工作着重于1-氨基寄生虫的发展，并证明了这些系统 可以用作代谢启动苯胺生物膜体。毒性特征，尤其是肝毒性，需要黑色 盒子警告在FDA批准的酪氨酸激酶抑制剂中很常见。苯胺，尽管它们是 通常在制药行业中使用，通常很容易被CYP450氧化。反应性的形成 氧化后的中间体通常会导致药物相互作用不良和特质毒性。 不幸的是，目前没有明确的苯胺等值线，迫使药物化学家不断使用 尽管已知对代谢衍生的脱靶毒性具有已知的倾向，但这些主题尽管已知。光化学策略 很容易合成1-氨基寄生虫。初步结果表明1- 尽管结构差异很大，但氨寄生虫基序仍具有与苯胺相似的化学空间。 这些结果已成为最初的概念证明，即1-的饱和碳环框架框架 Aminonorboranes可以用作可靠的苯胺生物膜固醇。该初步证据具有最佳位置 这个项目将我们的合成设计和发现实施到破坏性的翻译进展中。这会 可以通过开发新颖的1-氨基寄生虫基于溶瘤激酶的类似物来实现 抑制剂，拉帕替尼和厄洛替尼。这些等同质类似物预计将提供类似的抗抑制作用 疗效的同时避免了限制这些和其他癌症效用的不良代谢事件 化学疗法。因此，这项工作将验证1-氨基寄生虫作为苯胺生物蛋白酶的实用性，并提供 将药物开发范式从具有风险的芳族基序转移到更好的势头 容忍，饱和的构件。

项目成果

A One-Pot Photochemical Method for the Generation of Functionalized Aminocyclopentanes.

• DOI: 10.1021/acs.orglett.2c01483
• 发表时间: 2022-06-24
• 期刊: ORGANIC LETTERS
• 影响因子: 5.2
• 作者: Collins, James L., III;Staveness, Daryl;Sowden, Madison J.;Stephenson, Corey R. J.
• 通讯作者: Stephenson, Corey R. J.