ABSTRACT
Selective inhibition of Janus kinases (JAKs) is an arising strategy in drug discovery. Covalent inhibitors targeting a unique cysteine in JAK3 exhibit ultraselectivity among JAK family members. However, safety and tissue specific concerns still remain. A prodrug of a known JAK3 covalent inhibitor sensitive to H2O2 was designed and synthesized and its therapeutic effect was evaluated in the CIA (collagen-induced arthritis) mice model of RA (rheumatoid arthritis). The prodrug strategy relied on the introduction of a hydrogen peroxide-sensitive borate trigger group to avoid random covalent binding to thiol functionalities in biomacromolecules. The results show that the prodrug can be activated and released under pathophysiological concentration of H2O2. In addition, the prodrug demonstrated stability to the physiological environment. In comparison to the parent compound, the prodrug showed a similar therapeutic effect in the CIA model but notably exhibited lower toxicity and a larger therapeutic window.
ABSTRACT
A series of simplified berberine analogs was designed, synthesized, and evaluated for anti-inflammatory activity. SAR studies identified N-benzyltetrahydroisoquinoline 7d as a potent berberine analog. 7d suppressed LPS-induced inflammatory cytokine levels in both BV2 cells and primary microglia. Taken together, our results suggest that simplified BB analogs have therapeutic potential as a novel class of anti-neuroinflammatory agents.
