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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Optimization of First-in-Class Dual-Acting FFAR1/FFAR4 Allosteric Modulators with Novel Mode of Action. / Lückmann, Michael; Shenol, Aslihan; Nissen, Tinne A.D.; Petersen, Jacob E.; Kouvchinov, David; Schwartz, Thue W.; Frimurer, Thomas M.

In: ACS Medicinal Chemistry Letters, Vol. 13, No. 12, 2022, p. 1839-1847.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Lückmann, M, Shenol, A, Nissen, TAD, Petersen, JE, Kouvchinov, D, Schwartz, TW & Frimurer, TM 2022, 'Optimization of First-in-Class Dual-Acting FFAR1/FFAR4 Allosteric Modulators with Novel Mode of Action', ACS Medicinal Chemistry Letters, vol. 13, no. 12, pp. 1839-1847. https://doi.org/10.1021/acsmedchemlett.2c00160

APA

Lückmann, M., Shenol, A., Nissen, T. A. D., Petersen, J. E., Kouvchinov, D., Schwartz, T. W., & Frimurer, T. M. (2022). Optimization of First-in-Class Dual-Acting FFAR1/FFAR4 Allosteric Modulators with Novel Mode of Action. ACS Medicinal Chemistry Letters, 13(12), 1839-1847. https://doi.org/10.1021/acsmedchemlett.2c00160

Vancouver

Lückmann M, Shenol A, Nissen TAD, Petersen JE, Kouvchinov D, Schwartz TW et al. Optimization of First-in-Class Dual-Acting FFAR1/FFAR4 Allosteric Modulators with Novel Mode of Action. ACS Medicinal Chemistry Letters. 2022;13(12):1839-1847. https://doi.org/10.1021/acsmedchemlett.2c00160

Author

Lückmann, Michael ; Shenol, Aslihan ; Nissen, Tinne A.D. ; Petersen, Jacob E. ; Kouvchinov, David ; Schwartz, Thue W. ; Frimurer, Thomas M. / Optimization of First-in-Class Dual-Acting FFAR1/FFAR4 Allosteric Modulators with Novel Mode of Action. In: ACS Medicinal Chemistry Letters. 2022 ; Vol. 13, No. 12. pp. 1839-1847.

Bibtex

@article{c7c3f34a40c64e539b1dfb4b67a37899,
title = "Optimization of First-in-Class Dual-Acting FFAR1/FFAR4 Allosteric Modulators with Novel Mode of Action",
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. ",
keywords = "FFAR1, FFAR4, free fatty acid receptor, G-protein-coupled receptor, GPR120, GPR40",
author = "Michael L{\"u}ckmann and Aslihan Shenol and Nissen, {Tinne A.D.} and Petersen, {Jacob E.} and David Kouvchinov and Schwartz, {Thue W.} and Frimurer, {Thomas M.}",
note = "Funding Information: The Novo Nordisk Foundation Center for Basic Metabolic Research is supported by an unconditional grant (NNF10CC1016515) from the Novo Nordisk Foundation to the University of Copenhagen. This study was further supported by a Proof of Concept (PoC) grant (#0058362) from the Novo Nordisk Foundation. Publisher Copyright: {\textcopyright} 2022 The Authors. Published by American Chemical Society.",
year = "2022",
doi = "10.1021/acsmedchemlett.2c00160",
language = "English",
volume = "13",
pages = "1839--1847",
journal = "ACS Medicinal Chemistry Letters",
issn = "1948-5875",
publisher = "American Chemical Society",
number = "12",

}

RIS

TY - JOUR

T1 - Optimization of First-in-Class Dual-Acting FFAR1/FFAR4 Allosteric Modulators with Novel Mode of Action

AU - Lückmann, Michael

AU - Shenol, Aslihan

AU - Nissen, Tinne A.D.

AU - Petersen, Jacob E.

AU - Kouvchinov, David

AU - Schwartz, Thue W.

AU - Frimurer, Thomas M.

N1 - Funding Information: The Novo Nordisk Foundation Center for Basic Metabolic Research is supported by an unconditional grant (NNF10CC1016515) from the Novo Nordisk Foundation to the University of Copenhagen. This study was further supported by a Proof of Concept (PoC) grant (#0058362) from the Novo Nordisk Foundation. Publisher Copyright: © 2022 The Authors. Published by American Chemical Society.

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - FFAR1

KW - FFAR4

KW - free fatty acid receptor

KW - G-protein-coupled receptor

KW - GPR120

KW - GPR40

U2 - 10.1021/acsmedchemlett.2c00160

DO - 10.1021/acsmedchemlett.2c00160

M3 - Journal article

C2 - 36518697

AN - SCOPUS:85141602675

VL - 13

SP - 1839

EP - 1847

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

SN - 1948-5875

IS - 12

ER -

ID: 329249011