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
were constructed, and tofacitinib azo prodrugs 9 and 20a–20g were synthesized accordingly. The release studies
suggested that these systems could effectively release tofacitinib in vitro, and the 5-ASA–PABA–diamine system
could successfully realize the colon targeting of tofacitinib in vivo. Specifically, compound 20g displayed
a 3.67-fold decrease of plasma AUC(tofacitinib, 0–∞) and a 9.61-fold increase of colonic AUC(tofacitinib, 0–12h), compared with tofacitinib at a molar equivalent oral dose. Moreover,
mouse models suggested that compound 20g (1.5 mg/kg)
could achieve roughly the same efficacy against ulcerative colitis
compared with tofacitinib (10 mg/kg) and did not impair natural killer
cells. These results demonstrated the feasibility of compound 20g as an effective alternative to mitigate the systemic adverse
effects of tofacitinib, and 5-ASA–PABA–MAC and 5-ASA–PABA–diamine
systems were proven to be effective for colon-specific drug delivery.