Optimization of 4-amino-pyridazin-3(2H)-one as a valid core scaffold for FABP4 inhibitors

Giuseppe Floresta, Letizia Crocetti*, Renan Rodrigues de Oliveira Silva, Vincenzo Patamia, Francesca Mazzacuva, Yu Chee Sonia Chen, Claudia Vergelli, Agostino Cilibrizzi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Current clinical research suggests that fatty acid-binding protein 4 inhibitors (FABP4is), which are of biological and therapeutic interest, may show potential in treating cancer and other illnesses. We sought to uncover new structures through the optimization of the previously reported 4-amino and 4-ureido pyridazinone-based series of FABP4is as part of a larger research effort to create more potent FABP4 inhibitors. This led to the identification of 14e as the most potent analog with IC50 = 1.57 μM, which is lower than the IC50 of the positive control. Advanced modeling investigations and in silico absorption, distribution, metabolism, and excretion - toxicity calculations suggested that 14e represents a potential candidate for in vivo studies such as FABP4i.

Original languageEnglish
Article number2300314
JournalArchiv Der Pharmazie
Volume356
Issue number10
Early online date30 Jul 2023
DOIs
Publication statusPublished - Oct 2023

Keywords

  • computing assisted molecular design
  • FABP4
  • FABP4 inhibitors
  • fatty acid binding protein
  • pyridazinone

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