Discovery of a Colon-Targeted Azo Prodrug of Tofacitinib through the Establishment of Colon-Specific Delivery Systems Constructed by 5-ASA-PABA-MAC and 5-ASA-PABA-Diamine for the Treatment of Ulcerative Colitis

To mitigate the systemic adverse effects of tofacitinib, 5-ASA-PABA-MAC and 5-ASA-PABA-diamine colon-specific delivery systems wereconstructed, and tofacitinib azo prodrugs9and20a-20gwere synthesizedaccordingly. The release studies suggested that these systems could effectivelyrelease tofacitinibin vitro, and the 5-ASA-PABA-diamine system couldsuccessfully realize the colon targeting of tofacitinibin vivo. Specifically,compound20gdisplayed a 3.67-fold decrease of plasma AUC(tofacitinib, 0-infinity)anda 9.61-fold increase of colonic AUC(tofacitinib, 0-12h), compared with tofacitinib ata molar equivalent oral dose. Moreover, mouse models suggested thatcompound20g(1.5 mg/kg) could achieve roughly the same efficacy againstulcerative colitis compared with tofacitinib (10 mg/kg) and did not impairnatural killer cells. These results demonstrated the feasibility of compound20gas an effective alternative to mitigate the systemic adverse effects of tofacitinib,and 5-ASA-PABA-MAC and 5-ASA-PABA-diamine systems were proven tobe effective for colon-specific drug delivery.