Co-crystal structure guided array synthesis of PPARgamma inverse agonists

Area of Science:

• Endocrinology
• Metabolic Diseases
• Medicinal Chemistry

Background:

• Thiazolidinediones and carboxylic acids, like farglitazar, activate PPARγ.
• PPARγ activation is crucial for the anti-diabetic effects of these compounds, impacting glucose and lipid metabolism.
• Both pro- and anti-adipogenic PPARγ ligands demonstrate glucose and lipid-lowering effects in diabetic animal models.

Purpose of the Study:

• To explore novel PPARγ ligands with potential anti-diabetic properties.
• To investigate the activity of farglitazar analogues, specifically focusing on their interaction with PPARγ in mature adipocytes.
• To identify compounds exhibiting atypical inverse agonism of PPARγ.

Main Methods:

• Synthesis and characterization of 160 farglitazar analogues.
• Assessment of ligand activity on peroxisome proliferator-activated receptor gamma (PPARγ).
• Evaluation of compound effects in mature adipocytes to determine agonism/antagonism profiles.

Main Results:

• Discovery of farglitazar analogues with atypical inverse agonism of PPARγ.
• Identification of compounds demonstrating unique interactions with PPARγ in mature adipocytes.
• The synthesized analogues represent a novel chemical space for PPARγ modulation.

Conclusions:

• Atypical inverse agonism of PPARγ by novel farglitazar analogues presents a new therapeutic avenue.
• These findings contribute to understanding PPARγ ligand diversity and its role in metabolic regulation.
• Further research into these analogues may yield innovative treatments for diabetes and related metabolic disorders.