Design and Synthesis of Trisubstituted Imidazole Derivatives as Inhibitors of p38 Mitogen-Activated Protein Kinases

Abstract

The mitogen-activated protein kinase (MAPK) p38α is involved in the biosynthesis of the both pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), at the translational and transcriptional level that are implicated in the pathology of several chronic inflammatory diseases including rheumatoid arthritis. Previous studies have demonstrated that specific inhibitors of p38α MAP kinase suppress production of these cytokines from mononuclear cells, making this enzyme a very attractive target for novel inflammatory therapy. In this study, we synthesized a series of trisubstituted imidazole derivatives and evaluated their p38α MAP kinase inhibitory activity. Among them, compound 6b (IC_(50) = 2.80×10^(-8) M) showed the most significant p38α MAP kinase inhibition that is approximately 30-fold more potent than that of VX-702 (IC_(50) = 8.22 × 10^(-7) M).;p38 Mitogen-activated protein kinase (MAPK)는 pro-inflammatory cytokine인 TNF-α, IL-1β 생합성의 신호 전달 체계에 중추적인 역할을 하여 류마티스 관절염을 비롯한 심각한 만성 염증 질환을 유발하는 것으로 알려져 있다. 기존의 연구들이 p38α MAP kinase 저해제가 이런 cytokines의 생합성을 억제하는 것을 증명하여 p38α MAP kinase가 새로운 염증 질환 치료제의 target으로 부각되고 있다. 우리는 이번 연구에서, 기존의 p38α MAP kinase inhibitor들의 구조를 변형하여 효능을 높이기 위하여 trisubstituted imidazole 유도체들을 디자인하고 합성하였고, 이들 화합물의 p38α MAP kinase에 대한 IC50를 평가하였다．그 결과 6b (IC_(50)= 2.80 ×10^(-8) M)는 Vertex사의 VX-702 (IC_(50) = 8.22×10^(-7) M)와 비교하여 약 30배 높은 p38α MAP kinase inhibition 효과를 나타냈다.