Structure optimization of natural product piperine to obtain novel and potent analogs with anti-inflammation pain and urate-lowering effect

Abstract

Hyperuricemia is a metabolic disorder syndrome caused by a disorder of purine metabolism in the body, followed by urate crystal deposition leading to gouty arthritis, urate nephropathy, and kidney stones, collectively known as gout. Promoting uric acid stone dissolution by continuously reducing blood uric acid levels and reducing acute gout attacks in patients by controlling inflammatory pain reactions are identified as a potential therapy for gout. Starting from the natural product piperine, three analogs of novel piperine derivates were designed and synthesized to improve the anti-inflammation pain efficacy. Among this, compound 39 exhibited remarkable analgesic and urate-lowering effect in formalin-induced inflammatory pain model and hyperuricemic model, respectively. Besides, compound 39 exhibited a relatively potent TRPV1 antagonistic effect with an IC₅₀ = 33.06 ± 3.15 nM, and moderate to weak URAT1 (IC₅₀ = 22.51 ± 5.62 μM) and GLUT9 inhibitory activities (60.25 % at 50 μM). Further experiment showed that 39 exhibited high stability in vitro and in vivo, and its oral bioavailability was 34 %, with a more than 8 h T_1/2. Notably, compound 39 showed high selectivity over other ion channel including hERG which indicated a high safety index. Furthermore, no significant acute damage was observed at the liver microsome, cellular and animal levels. In the long-term administration experiment of hyperuricemia model mice, it was confirmed that 39 could reverse the tissue damage and inflammation caused by high uric acid. Overall, these findings identified a promising candidate to target the pathogenesis of gout by simultaneously suppressing pian and the reabsorption of uric acid.