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
Jiaxing Zhao, Bing Zhang, Qing Mao, Kunqi Ping, Peng Zhang, Fengwei Lin, Dan Liŭ, Feng Yao, Ming Sun, Yan Zhang, Qiu Hua Li, Tingjian Zhang, Yanhua Mou, Shaojie Wang
Abstract
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.