Innovative targets for circadian drug discovery: REV-ERBalpha and RORalpha

昼夜节律药物发现的创新靶标：REV-ERBalpha 和 RORalpha

• 批准号: EP/H031111/2
• 负责人: Nicholas Tomkinson
• 金额: $ 154.21万
• 依托单位: University of Strathclyde
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FH031111%2F2
• 关键词: Innovative; targets; circadian; drug; discovery

Humans are rhythmic beings, with daily sleep/wake cycles affecting almost every aspect of physiology and behaviour. Our master circadian clock is known to reside in the suprachiasmatic nuclei (SCN) of the hypothalamus. Via multiple pathways, output from the SCN synchronizes peripheral oscillators throughout the body. The discovery of the molecular components of the core clock has provided new insight into the link between circadian biology and chronic diseases, but has not been exploited for drug discovery. With this work we will prepare chemical probes for the clock proteins REV-ERBalpha and RORalpha, characterise their activity in models of inflammation, and deliver lead optimised molecules for clinical development.

人类是有节奏的生物，每天的睡眠/觉醒周期几乎影响着生理和行为的各个方面。我们的主生物钟位于下丘脑的视交叉上核（SCN）。通过多个通路，SCN的输出将外周振荡器传递到全身。核心时钟分子组成的发现为昼夜节律生物学和慢性疾病之间的联系提供了新的见解，但尚未用于药物发现。通过这项工作，我们将为时钟蛋白REV-ERBalpha和RORalpha制备化学探针，在炎症模型中验证它们的活性，并为临床开发提供领先的优化分子。

项目成果

Synthesis of dibenzylamino-1-methylcyclohexanol and dibenzylamino-1-trifluoromethylcyclohexanol isomers.

二苄氨基-1-甲基环己醇和二苄氨基-1-三氟甲基环己醇异构体的合成。

• DOI: 10.1039/c5ob01924a
• 发表时间: 2016
• 期刊: Organic & biomolecular chemistry
• 影响因子: 3.2
• 作者: Jones DH

TRANSITION METAL-MEDIATED SYNTHESIS OF OXAZOLES

• DOI: 10.3987/rev-14-808
• 发表时间: 2014-11-01
• 期刊: HETEROCYCLES
• 影响因子: 0.6
• 作者: Bresciani, Stefano;Tomkinson, Nicholas C. O.
• 通讯作者: Tomkinson, Nicholas C. O.

Preparation of Symmetrical and Nonsymmetrical Fluorene ­Sulfonamide Scaffolds

对称和非对称芴磺酰胺支架的制备

• DOI: 10.1055/s-0036-1588916
• 发表时间: 2016
• 期刊: Synlett
• 影响因子: 2
• 作者: Tomkinson N