Novel Dual Soft Drug Strategy Enables Development of Topical Androgen Receptor Antagonists with Enhanced Efficacy and Optimized Safety for Androgenetic Alopecia.

Reconciling therapeutic efficacy with a low risk of systemic toxicity persists as a critical hurdle in developing topical AR antagonists for AGA. Our first-generation soft drug AR antagonist 14-P1 showed pyrilutamide-comparable efficacy with enhanced pharmacokinetics and safety, yet required high dosing due to suboptimal AR antagonism. Here, structural optimization of 14-P1 focused on enhancing intrinsic AR antagonism through thiohydantoin scaffold refinement. Additionally, the implementation of a dual soft drug design strategy yielded the best-performing candidate 39, demonstrating potent AR antagonism (IC50 = 20.6 ± 2.3 nM) and favorable PK profiles. In a hair-growth mouse model, 0.5% 39 achieved comparable efficacy to 0.5% pyrilutamide with accelerated response kinetics (14-day vs 21-day onset) and preserved safety. This dual metabolic inactivation strategy successfully reconciles therapeutic potency with a low risk of systemic toxicity, providing a paradigm for next-generation topical AR antagonist development.