首页|Optimization of First-in-Class Dual-Acting FFAR1/FFAR4 Allosteric Modulators with Novel Mode of Action
Optimization of First-in-Class Dual-Acting FFAR1/FFAR4 Allosteric Modulators with Novel Mode of Action
扫码查看
点击上方二维码区域，可以放大扫码查看
原文链接
NSTL
Amer Chemical Soc
? 2022 American Chemical Society. All rights reserved.The free fatty acid receptors FFAR1 and FFAR4 are considered promising therapeutic targets for management of metabolic and inflammatory diseases. However, there is a need for entirely novel chemical scaffolds, since many of the highly similar lipophilic chemotypes in development have been abandoned by the pharmaceutical industry, due to toxic effects on hepatocytes and β-cells. Our group has recently reported the discovery of a 1,3,5-triazine-2-amine-based compound that acts as an allosteric agonist on FFAR1. Here, we present the synthesis and investigation of the structure-activity relationship of an extensive set of analogues of which many display dual-acting agonist properties for both FFAR1 and FFAR4. In several rounds of optimization, we discovered multiple analogues with single-digit nanomolar potency on FFAR1. Pending additional optimization for metabolic stability, the compounds in this study present novel ways of providing beneficial glycemic control while avoiding the notorious toxicity challenges associated with previously identified chemotypes.
Novo Nordisk Foundation Center for Basic Metabolic Research University of Copenhagen
Department of Basic and Clinical Neuroscience Maurice Wohl Clinical Neuroscience Institute Institute of Psychiatry Psychology and Neuroscience King's College London
NSTL
Amer Chemical Soc
