2. Academic Validation
  3. FFAR1/GPR40: One target, different binding sites, many agonists, no drugs, but a continuous and unprofitable tug-of-war between ligand lipophilicity, activity, and toxicity

FFAR1/GPR40: One target, different binding sites, many agonists, no drugs, but a continuous and unprofitable tug-of-war between ligand lipophilicity, activity, and toxicity

  • Bioorg Med Chem Lett. 2021 Jun 1;41:127969. doi: 10.1016/j.bmcl.2021.127969.
Paolo Governa 1,  Maria Cristina Caroleo 2,  Gabriele Carullo 1,  Francesca Aiello 3,  Erika Cione 4,  Fabrizio Manetti 5
Affiliations

Affiliations

  • 1 Department of Biotechnology, Chemistry and Pharmacy-Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, I-53100 Siena, Italy.
  • 2 Department of Pharmacy, Health and Nutritional Sciences-Department of Excellence 2018-2022, University of Calabria, Ed. Polifunzionale, I-87036 Arcavacata di Rende, CS, Italy.
  • 3 Department of Pharmacy, Health and Nutritional Sciences-Department of Excellence 2018-2022, University of Calabria, Ed. Polifunzionale, I-87036 Arcavacata di Rende, CS, Italy. Electronic address: francesca.aiello@unical.it.
  • 4 Department of Pharmacy, Health and Nutritional Sciences-Department of Excellence 2018-2022, University of Calabria, Ed. Polifunzionale, I-87036 Arcavacata di Rende, CS, Italy. Electronic address: erika.cione@unical.it.
  • 5 Department of Biotechnology, Chemistry and Pharmacy-Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, I-53100 Siena, Italy. Electronic address: fabrizio.manetti@unisi.it.
PMID: 33771587 DOI: 10.1016/j.bmcl.2021.127969
Abstract

The progress made so far in the elucidation of the structure of Free Fatty Acid Receptor 1 (FFAR1) and its secondary and ternary complexes with partial and full allosteric ligands led to the discovery of various putative binding regions on the FFAR1 surface. Attempts to develop FFAR1 agonists culminated with the identification of TAK-875 (1), whose phase 3 clinical trials were terminated due to potential liver toxicity. In the search of safer agonists, numerous classes of new compounds were designed, synthesized, and tested. Chemical decoration of the scaffolds was rationalized to reach a good balance between lipophilicity, activity, and toxicity. Today, targeting FFAR1 with positive modulators represents an attractive pharmacological tool for the treatment of type 2 diabetes mellitus (T2DM), mainly because of the lack of hypoglycaemic side effects associated with several antidiabetic drugs currently available. Moreover, considering the involvement of FFAR1 in many physio-pathological processes, its agonists are also emerging as possible therapeutic tools for alleviating organ inflammation and fibrosis, as well as for the treatment of CNS disorders, such as Alzheimer's disease and dementia.

Keywords

Allosteric agonists; FFAR1/GPR40; TAK-875; Type 2 diabetes mellitus.

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