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

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.

Recent advances in self-immolative linkers and their applications in polymeric reporting systems

“…for controlled release of Tofacitinib for the treatment of ulcerative colitis. 69,70 Senter et al have also flagged the importance of the leaving group during an investigation into release of a reporter group linked through an alcohol moiety and have shown the effect on self-immolative ability, elimination rates, and conjugate stability. 71 In this study, 4-aminobenzyl ether-based conjugates were studied with the N-protected dipeptide trigger group, benzyloxycarbonylvaline-citrulline (Z-val-cit).…”

Novel Para-Aminobenzoic Acid Analogs and Their Potential Therapeutic Applications

“…Several p-aminobenzoic acid derivatives have been evaluated against acetylcholinesterase (AChE) for AD treatment. Moreover, drugs containing PABA moiety are safe and tolerable [24]. The evaluation of several derivatives of p-and m-aminobenzoic acid as inhibitors of cholinesterase suggested the greater activity of p-substitution derivatives than other analogs [25].…”

Colonic drug delivery: Formulating the next generation of colon-targeted therapeutics

“…These observations have been associated with the sulfapyridine component of the prodrug [29], sparking subsequent development of other 5-ASA prodrugs, including olsalazine and balsalazide [30,31]. The prodrug strategy is still utilised for colonic delivery, for example an azo prodrug of tofacitinib was recently shown to effectively treat a mouse model of IBD [32]. Similarly, gut restriction of molecules (particularly peptides) could enable local colonic action by preventing systemic absorption [33].…”