Design and Synthesis of Anemoside B4 Derivatives as Pyruvate Carboxylase-Targeting Therapeutic Agents for Atopic Dermatitis.

Although injectable anemoside B4 (AB4) has therapeutic potential for atopic dermatitis (AD), its clinical use is restricted by safety and pharmacokinetic issues. Therefore, we designed 42 AB4 derivatives, established a preliminary SAR for anti-inflammatory and antiallergic activities, and selected three promising compounds for in vivo evaluation in an AD mouse model, leading to the identification of B4-39 as the lead compound. In a DNCB-induced AD mouse model, topical B4-39 (6.6 mg/kg) was more effective than dexamethasone and free from its side effects, while matching the efficacy of crisaborole at a much lower dose and providing better skin barrier repair. Mechanistically, B4-39 targets pyruvate carboxylase (PC)─a novel therapeutic target in AD─modulating the TCA cycle to suppress dendritic cell activation and concurrently inhibiting NF-κB and NLRP3 inflammasome signaling. Given its enhanced efficacy, steroid-sparing safety, novel PC-targeted action, and favorable topical delivery, B4-39 is a highly promising candidate for AD treatment.