2. Academic Validation
  3. Design, synthesis and pharmacological evaluation of multitarget GPR40 agonists/HDAC6 inhibitors for Alzheimer's disease

Design, synthesis and pharmacological evaluation of multitarget GPR40 agonists/HDAC6 inhibitors for Alzheimer's disease

  • Eur J Med Chem. 2025 Jun 13:296:117868. doi: 10.1016/j.ejmech.2025.117868.
Pedro de Sena M Pinheiro 1,  Francesca de Chirico 2,  Manuela Loi 3,  Stefania Trazzi 3,  Elisabetta Ciani 3,  Daniel Alencar Rodrigues 4,  Marina Amaral Alves 5,  Lídia Moreira Lima 6,  Andrea Milelli 7,  Barbara Monti 8,  Carlos Alberto Manssour Fraga 9,  Maria Laura Bolognesi 10
Affiliations

Affiliations

  • 1 Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil; Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil; Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Bologna, Italy; Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil. Electronic address: pedro.pinheiro@icb.ufrj.br.
  • 2 Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, Genova, 16132, Italy.
  • 3 Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
  • 4 School of Pharmacy and Biomolecular Sciences (PBS), Royal College of Surgeons in Ireland, 1st Floor Ardilaun House Block B 111 St Stephen's Green, Dublin 2, Ireland.
  • 5 Walter Mors Institute of Research on Natural Products, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
  • 6 Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil; Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil; Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil.
  • 7 Department for Life Quality Studies, University of Bologna, Rimini, Italy.
  • 8 Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
  • 9 Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil; Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil; Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Bologna, Italy; Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil.
  • 10 Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Bologna, Italy. Electronic address: marialaura.bolognesi@unibo.it.
PMID: 40541115 DOI: 10.1016/j.ejmech.2025.117868
Abstract

The discovery of new therapeutic agents for the treatment of neurodegenerative diseases-particularly Alzheimer's disease (AD) -remains one of the most challenging areas in medicinal chemistry. Given the multifactorial nature of these disorders, the rational design of multitarget-directed ligands (MTDLs) is gaining increasing attention, underscoring the importance of exploring novel target combinations. In this study, we report the design of the first-in-class multitarget compounds that function as dual GPR40 agonists and HDAC6 inhibitors-a novel strategy aimed at modulating neuroinflammation in AD. Among them, compound 4e exhibited potent activity, with an EC50 of 22 nM for GPR40 activation and an IC50 of 73 nM for HDAC6 inhibition. This balanced dual profile was corroborated in cell-based assays, where compound 4e significantly increased acetylated tubulin and ERK phosphorylation levels in SH-SY5Y cells. Furthermore, compound 4e demonstrated immunomodulatory effects on microglia, highlighting its potential as a chemical starting point for targeting neuroinflammation and, ultimately, neurodegeneration.

Keywords

Dementia; Dual compounds; Free fatty acid receptor 1; Histone deacetylase 6; Multitarget; Neurodegeneration; Neuroinflammation.

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