Optimization of potent, selective and orally bioavailable biphenyl scaffold as FABP4 inhibitors for anti-inflammation

Area of Science:

• Biochemistry
• Pharmacology
• Medicinal Chemistry

Background:

• Fatty-acid binding protein 4 (FABP4) drives metabolic inflammatory diseases like obesity and diabetes.
• Existing FABP4 inhibitors lack selectivity, efficacy, and optimal properties for clinical use.

Purpose of the Study:

• To systematically optimize biphenyl scaffold molecules as potent FABP4 inhibitors.
• To identify a selective, orally bioavailable FABP4 inhibitor with therapeutic potential.

Main Methods:

• Systematic chemical optimization of biphenyl scaffolds.
• In vitro enzymatic assays to determine inhibitor selectivity (FABP4 vs. FABP3).
• In vivo pharmacokinetic and anti-inflammatory studies in a mouse model.

Main Results:

• A novel biphenyl compound, 10g, was identified as a potent FABP4 inhibitor (K_i = 0.51 μM).
• Compound 10g demonstrated high selectivity for FABP4 over FABP3 (K_i = 33.01 μM).
• Compound 10g exhibited excellent oral bioavailability (F% = 89.4%) and significant in vivo anti-inflammatory efficacy.

Conclusions:

• Compound 10g represents a promising therapeutic candidate for treating FABP4-driven inflammatory diseases.
• The optimized biphenyl scaffold offers a viable strategy for developing selective FABP4 inhibitors.
• Further development of compound 10g may lead to novel treatments for obesity, diabetes, and related conditions.