Optimization of First-in-Class Dual-Acting FFAR1/FFAR4 Allosteric Modulators with Novel Mode of Action

Michael Lückmann, Aslihan Shenol, Tinne A.D. Nissen, Jacob E. Petersen, David Kouvchinov, Thue W. Schwartz, Thomas M. Frimurer*

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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Abstract

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.

OriginalsprogEngelsk
TidsskriftACS Medicinal Chemistry Letters
Vol/bind13
Udgave nummer12
Sider (fra-til)1839-1847
ISSN1948-5875
DOI
StatusUdgivet - 2022

Bibliografisk note

Publisher Copyright:
© 2022 The Authors. Published by American Chemical Society.

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