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.

在激酶抑制剂开发中通过使用1-氨基-1，2-二苯并咪唑改善代谢稳定性概况 作为苯胺生物电子等排体的氨基降冰片烷 摘要 拟议的工作重点是1-氨基降冰片烷的发展和证明，这些系统 可以作为代谢惰性的苯胺生物电子等排体。毒性特征，特别是肝毒性，需要黑色 框警告在FDA批准的酪氨酸激酶抑制剂中是常见的。苯胺，虽然它们是 通常用于制药工业，通常容易被CYP 450氧化。形成反应性 中间体在氧化时通常导致不利的药物-药物相互作用和特异质毒性。 不幸的是，目前还没有明确的等排体苯胺，迫使药物化学家继续使用 这些基序尽管已知倾向于代谢衍生的脱靶毒性。一种光化学策略， 已经开发并发表了易于合成的1-氨基降冰片烷。初步结果表明，1- 氨基降冰片烷基序占据与苯胺类似的化学空间，尽管它们具有显著的结构差异。 这些结果已经作为初步的概念验证，即1-羟基-2-甲基-3-甲基-4-（4-甲基-2-苯基）-2-（4 氨基降冰片烷可以用作可靠的苯胺生物电子等排体。初步证据显示 该项目旨在将我们的合成设计和发现转化为颠覆性的转化进展。这将 通过开发新的基于1-氨基降冰片烷的溶瘤激酶类似物来实现 抑制剂，拉帕替尼和厄洛替尼。预期这些等排类似物提供类似的抗肿瘤活性。 同时避免限制这些和其他癌症效用的不良代谢事件 化疗因此，这项工作将验证1-氨基降冰片烷作为苯胺生物电子等排体的实用性，并提供 将药物开发范式从充满风险的芳香基序转变为更好的芳香基序所需的动力， 耐受性和饱和度

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.