Synthesis and Biological Evaluation of Novel (1,5-Naphthyridin-2-yl)-1H-pyrazoles and -imidazoles as Inhibitors of Transforming Growth Factor-β1 Type I Receptor

Abstract

Clinically, there is a great need for small molecule inhibitors that could control pathogenic effects of transforming growth factor-β (TGF-β). Inhibition of TGF-β signaling would be predicted to enhance re-epithelialization of cutaneous wounds and reduce scarring fibrosis. Selective small molecule inhibitors of the TGF-β signaling pathway developed for therapeutics will also be powerful tools in experimentally dissecting this complex pathway, especially its cross-talk with other signaling pathways. In our study, we have synthesized a series of (1,5-naphthyridin-2-yl)-1H-pyrazoles and -imidazoles and evaluated their ALK5 inhibitory activity in the luciferase reporter assays. Among them, 3-((3-(6-methylpyridin-2-yl)-4-(1,5-naphthyridin-2-yl)-1H-pyrazol-1-yl)methyl)benzo- nitrile (7a) (p3TP-Luciferase, 79%; SBE-Luciferase, 71%; ARE-Luciferase, 62%) and 3-((3-(6-methylpyridin-2-yl)-4-(1,5-naphthyridin-2-yl)-1H-pyrazol-1-yl)-methyl)benzamide (9a) (p3TP-Luciferase, 80%; SBE-Luciferase, 70%; ARE-Luciferase, 57%) displayed the most significant ALK5 inhibition at 0.1 µM, that is similar to that of SB-525334 (p3TP-Luciferase, 71%; SBE-Luciferase, 74%; ARE-Luciferase, 45%).;임상적으로 TGF-β의 병리학적인 효과나 정상적인 반응을 조절하는 물질 개발의 필요성이 제기되고 있다. TGF-β 신호 전달체계를 억제하는 것은 피부 상처의 재구성을 촉진시키고, 흉터의 섬유화를 억제할 것으로 기대할 수 있다. TGF-β 신호전달 체계의 선택적인 억제제들이 질병 치료의 목적으로 개발되었고, 이는 TGF-β의 신호전달과 다른 신호전달 경로와의 교차 작용을 실험적으로 분석하는데 쓸모 있는 도구가 될 것이다. 이번 연구를 통해 우리는 luciferase reporter assay 에서 ALK5의 억제 효능을 알아보기 위해 (1,5-naphthyridin-2-yl)-1H-pyrazoles 과 –imidazoles의 유도체 들을 합성하고 평가하였다. 그 중에서 3-((3-(6-methylpyridin-2-yl)-4-(1,5-naphthyridin-2-yl)-1H-pyrazol-1-yl)methyl)benzo- nitrile (7a) (p3TP-Luciferase, 79%; SBE-Luciferase, 71%; ARE-Luciferase, 62%)와 3-((3-(6-methylpyridin-2-yl)-4-(1,5-naphthyridin-2-yl)-1H-pyrazol-1-yl)-methyl)benzamide (9a) (p3TP-Luciferase, 80%; SBE-Luciferase, 70%; ARE-Luciferase, 57%)가 0.1 µM 에서 SB-525334 (p3TP-Luciferase, 71%; SBE-Luciferase, 74%; ARE-Luciferase, 45%)와 비슷한 ALK5 억제 작용을 보였다.