Structure optimization of a new class of PPARγ antagonists

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Molecular Biology

Background:

• Peroxisome proliferator-activated receptor gamma (PPARγ) modulators are utilized for treating cancers, metabolic disorders, and inflammatory diseases.
• PPARγ antagonists are less explored than agonists, with limited therapeutic options despite demonstrated immunomodulatory effects.
• The novel competitive PPARγ antagonist MTTB (T-10017) shows promise, contrasting with irreversible inhibitors like GW9662.

Purpose of the Study:

• To investigate the structure-activity relationships (SAR) of the MTTB scaffold.
• To enhance the physicochemical and drug-like properties of MTTB.
• To identify novel potent PPARγ antagonists with improved pharmacokinetic profiles.

Main Methods:

• Synthesis and characterization of 34 new MTTB derivatives.
• Evaluation of competitive antagonism against rosiglitazone-mediated PPARγ activation.
• Transactivation assays in HEK293T cells to determine IC50 values.

Main Results:

• MTTB demonstrated competitive antagonism of PPARγ ligand binding domain (PPARγLBD) with an IC50 of 4.3 µM against 1 µM rosiglitazone.
• 34 novel derivatives were synthesized and characterized based on the MTTB scaffold.
• Two potent compounds, T-10075 and T-10106, exhibited significantly improved drug-like properties and promising pharmacokinetics.

Conclusions:

• The study successfully optimized the MTTB scaffold, yielding potent PPARγ antagonists.
• Compounds T-10075 and T-10106 represent promising candidates for further therapeutic development.
• This research contributes to the development of a new class of PPARγ antagonists with improved drug profiles.