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

  • J Med Chem. 2022 Mar 24;65(6):4926-4948. doi: 10.1021/acs.jmedchem.1c02166.
Jiaxing Zhao  1 ,  Bing Zhang  1 ,  Qing Mao  1 ,  Kunqi Ping  1 ,  Peng Zhang  1 ,  Fengwei Lin  1 ,  Dan Liu  2 ,  Yao Feng  1 ,  Ming Sun  1 ,  Yan Zhang  3 ,  Qiu Hua Li  1 ,  Tingjian Zhang  4 ,  Yanhua Mou  3 ,  Shaojie Wang  1
Affiliations
  • 1. Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Culture Road, Shenhe District, Shenyang 110016, China.
  • 2. Shenyang Hinewy Pharmaceutical Technology Co., Ltd., 41 Liutang Road, Shenhe District, Shenyang 110016, China.
  • 3. Department of Pharmacology, Shenyang Pharmaceutical University, 103 Culture Road, Shenhe District, Shenyang 110016, China.
  • 4. School of Pharmacy, China Medical University, 77 Puhe Road, North New Area, Shenyang 110122, China.
PMID: 35275619 DOI: 10.1021/acs.jmedchem.1c02166
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.

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