Discovery and evaluation of SIPI11594: a novel mitochondrial pyruvate carrier inhibitor with anti-hair loss efficacy.

Inhibition of the mitochondrial pyruvate carrier (MPC) is a promising strategy to promote hair follicle stem cell activation via lactate production for treating alopecia. To identify new MPC inhibitors, we designed and synthesized 32 novel α-cyano-4-hydroxycinnamate derivatives based on a N1-arylmethylpyridine compound 4I. Structure-activity relationship analysis identified C4-substitution on the indole ring as crucial for potency, leading to the selection of the C4-fluoro-substituted derivative 5k (also named SIPI11594) as an optimal lead. 5k showed superior cellular lactate production-enhancing activity compared to UK-5099 and 4a. Molecular docking predicted stable binding to the MPC active site. The compound exhibited excellent stability in topical formulations and metabolic stability, and in a depilated C57BL/6J mouse model, topical 5k significantly accelerated hair regrowth and anagen entry, outperforming UK-5099. Preliminary safety assessments indicated no skin irritation and negligible hERG inhibition. Collectively, these findings identify 5k as a novel lead compound with promising activity and preliminary safety profile, warranting further optimization and validation as a potential topical agent for alopecia.