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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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Optimization of First-in-Class Dual-Acting FFAR1/FFAR4 Allosteric Modulators with Novel Mode of Action
Michael Lückmann1, Aslihan Shenol1, Tinne A D Nissen2
1Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark.
ACS Medicinal Chemistry Letters
|December 15, 2022
Summary
Researchers developed novel 1,3,5-triazine-2-amine compounds targeting free fatty acid receptors (FFAR1 and FFAR4) for metabolic diseases. These compounds show promise for glycemic control, avoiding toxic side effects of earlier drug candidates.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Drug Discovery
Background:
- Free fatty acid receptors (FFAR1 and FFAR4) are key targets for metabolic and inflammatory diseases.
- Existing lipophilic drug candidates face challenges due to hepatocyte and beta-cell toxicity.
- Novel chemical scaffolds are crucial for developing safer therapeutics.
Purpose of the Study:
- To synthesize and investigate novel 1,3,5-triazine-2-amine analogues.
- To explore structure-activity relationships for FFAR1 and FFAR4 agonism.
- To identify compounds with improved safety profiles for metabolic disease treatment.
Main Methods:
- Synthesis of an extensive library of 1,3,5-triazine-2-amine analogues.
- Structure-activity relationship (SAR) studies to optimize compound potency.
- Evaluation of dual agonism for FFAR1 and FFAR4.
Main Results:
- Discovery of multiple analogues with single-digit nanomolar potency on FFAR1.
- Identification of compounds exhibiting dual agonist activity for FFAR1 and FFAR4.
- Demonstration of a novel chemical scaffold with potential for safer glycemic control.
Conclusions:
- The 1,3,5-triazine-2-amine scaffold offers a promising new chemical class for targeting FFAR1 and FFAR4.
- Optimized analogues display high potency and dual agonism, addressing limitations of previous chemotypes.
- Further optimization for metabolic stability could lead to effective treatments for metabolic disorders with reduced toxicity.
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