Advancing Mitochondrial Therapeutics: Synthesis and Pharmacological Evaluation of Pyrazole-Based Inhibitors Targeting the Mitochondrial Pyruvate Carrier

The study synthesized approximately 50 pyrazole-based inhibitors targeting the mitochondrial pyruvate carrier (MPC) to improve treatment for metabolic diseases, certain cancers, neurodegeneration, and hair loss. These new inhibitors were designed to enhance specificity and pharmacokinetic properties by incorporating structural modifications that reduce their potential to act as Michael acceptors. Unlike thiazolidinedione MPC inhibitors, these compounds do not activate the nuclear receptor PPARγ. The inhibitors demonstrated potential as therapeutic candidates for metabolic dysfunction-associated steatohepatitis (MASH) by directly inhibiting stellate cell activation. Molecular modeling identified critical chemical determinants for MPC inhibition, resulting in potent, specific inhibitors with excellent physicochemical properties, high solubility, and metabolic stability in human liver microsomes.