Delving into the Latest Updates on FXR/LIFR modulators(Università degli Studi di Napoli Federico II) with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Compound 3a(Università degli Studi di Napoli Federico II)

Target

FXR x LIFR

Mechanism

FXR agonists(Bile acid receptor FXR agonists), LIFR inhibitors(LIF receptor subunit alpha inhibitors)

Therapeutic Areas

Digestive System DisordersOther Diseases

Active Indication

Fibrosis, Liver

Inactive Indication-

Originator Organization

Università degli Studi di Napoli Federico II

Active Organization

Università degli Studi di Napoli Federico II

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC24H17Cl2NO4

InChIKeyFVJFATSNWFWEGK-UHFFFAOYSA-N

CAS Registry2409154-23-8

Author: Bordoni, Martina ; Massa, Carmen ; Morretta, Elva ; Zampella, Angela ; Finamore, Claudia ; Catalanotti, Bruno ; Spinelli, Lucio ; Cassiano, Chiara ; Lupia, Antonio ; Biagioli, Michele ; Fiorillo, Bianca ; Monti, Maria Chiara ; Sepe, Valentina ; Fiorucci, Stefano ; Rapacciuolo, Pasquale ; Moraca, Federica ; Urbani, Ginevra ; Marchianò, Silvia ; Giorgio, Cristina Di

Although multiple approaches have been suggested, treating mild-to-severe fibrosis in the context of metabolic dysfunction associated with liver disease (MASLD) remains a challenging area in drug discovery. Pathogenesis of liver fibrosis is multifactorial, and pathogenic mechanisms are deeply intertwined; thus, it is well accepted that future treatment requires the development of multitarget modulators. Harnessing the 3,4,5-trisubstituted isoxazole scaffold, previously described as a key moiety in Farnesoid X receptor (FXR) agonism, herein we report the discovery of a novel class of hybrid molecules endowed with dual activity toward FXR and the leukemia inhibitory factor receptor (LIFR). Up to 27 new derivatives were designed and synthesized. The pharmacological characterization of this series resulted in the identification of 3a as a potent FXR agonist and LIFR antagonist with excellent ADME properties. In vitro and in vivo characterization identified compound 3a as the first-in-class hybrid LIFR inhibitor and FXR agonist that protects against the development of acute liver fibrosis and inflammation.

100 Deals associated with FXR/LIFR modulators(Università degli Studi di Napoli Federico II)

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