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-羟色胺改善酶抑制剂开发中的代谢稳定性 作为苯胺生物同位素体的氨基硼纳米化合物 摘要 拟议的工作重点是开发1-氨基硼烷，并演示这些系统 可作为代谢性惰性苯胺生物等位体。毒性特征，特别是肝脏毒性，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 通常用于制药行业，往往容易被CYP450氧化。反应性的形成 中间体的氧化往往会导致不良的药物相互作用和特殊的毒性。 不幸的是，目前还没有明确的苯胺等位线，迫使药用化学家继续使用 这些基序尽管有代谢的已知倾向，但产生了非靶标毒性。一种光化学策略来 已开发并发表了易于合成的1-氨基硼纳米化合物。初步结果表明，1- 氨基冰片基序占据了与苯胺相似的化学空间，尽管它们的结构有很大的差异。 这些结果已作为初步的概念证明，饱和碳环框架的1- 氨基硼烷可以作为一种可靠的苯胺生物同工酶。这一初步证据表明， 这个项目旨在将我们的合成设计和发现转化为颠覆性的翻译进步。这将是 通过开发新的基于1-氨基冰片的溶瘤激酶类似物来实现 抑制剂，拉帕替尼和埃洛替尼。这些等构体类似物有望提供类似的抗肿瘤作用。 在避免限制这些癌症和其他癌症的效用的不良代谢事件的同时保持疗效 化疗。因此，这项工作将验证1-氨基硼纳米作为苯胺生物同位素体的用途，并提供 将药物开发范式从高风险的芳香族主题转变为更好的- 可容忍的饱和构建块。

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.