Novel 2-Phenyl-1H-Pyrrole Derivatives as Mitochondrial Pyruvate Carrier Inhibitors to Treat Hair Loss.

Hair follicle stem cells (HFSCs) play the primary role in the regulation of the hair growth cycle. Premature termination of the anagen phase accelerates the transition of hair follicles into the catagen and telogen phases, leading to hair loss. Inhibiting the mitochondrial pyruvate carrier (MPC), which prevents pyruvate from entering mitochondria, enhances lactate synthesis. This activates HFSCs and initiates a new hair growth cycle. To develop safer and more effective MPC inhibitors, we designed and synthesized a series of 2-phenyl-1H-pyrrole derivatives based on UK5099 and JXL066 by scaffold hopping and structural optimization strategies. In vitro lactate release assay identified 14 compounds that exhibited superior biological activity compared to UK5099, with 5a being the most potent compound. The ADMET predictions suggested that 5a possesses low toxicity and moderate skin permeability, supporting its suitability for topical dermal formulations. Further evaluation demonstrated 5a had good stability in topical formulation and low skin irritation in repeated acute irritation tests. Hair regrowth experiments in C57BL/6J mice showed that 5a significantly promoted hair regrowth and accelerated the transition from telogen to anagen, accompanied by increased hair follicle density. These findings validate MPC as a promising target and highlight 5a as a potential therapeutic agent for the treatment of hair loss.