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

doi:10.1002/ardp.202300314

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

Research output: Contribution to journal › Article › peer-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 language	English
Article number	2300314
Number of pages	14
Journal	Archiv der Pharmazie
Volume	356
Issue number	10
Early online date	30 Jul 2023
DOIs	https://doi.org/10.1002/ardp.202300314
Publication status	Published - 31 Oct 2023
Externally published	Yes

Bibliographical note

Funding Information:
This research has received funding for a scholarship to R.R.d.O.S from the Coordination for the Improvement of Higher Education Personnel—Brazil (CAPES‐PRINT, funding number 88887.570120/2020‐00).

Funding

This research has received funding for a scholarship to R.R.d.O.S from the Coordination for the Improvement of Higher Education Personnel—Brazil (CAPES‐PRINT, funding number 88887.570120/2020‐00). This research has received funding for a scholarship to R.R.d.O.S from the Coordination for the Improvement of Higher Education Personnel—Brazil (CAPES-PRINT, funding number 88887.570120/2020-00).

Funders	Funder number
CAPES-PRINT
CAPES‐PRINT	88887.570120/2020‐00
Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior

Keywords

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

ASJC Scopus subject areas

Pharmaceutical Science
Drug Discovery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/ardp.202300314Licence: CC BY

Cite this

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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.",

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author = "Giuseppe Floresta and Letizia Crocetti and Silva, {Renan Rodrigues de Oliveira} and Vincenzo Patamia and Francesca Mazzacuva and Chen, {Yu Chee Sonia} and Claudia Vergelli and Agostino Cilibrizzi",

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AU - Patamia, Vincenzo

AU - Mazzacuva, Francesca

AU - Chen, Yu Chee Sonia

AU - Vergelli, Claudia

AU - Cilibrizzi, Agostino

N1 - Funding Information: This research has received funding for a scholarship to R.R.d.O.S from the Coordination for the Improvement of Higher Education Personnel—Brazil (CAPES‐PRINT, funding number 88887.570120/2020‐00).

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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