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Synthesis and Biological Evaluation of Novel 2-Pyridyl Substituted Imidazole Sulfonamide Derivatives as Inhibitors of Transforming Growth Factor-β1 Type I Receptor

Title
Synthesis and Biological Evaluation of Novel 2-Pyridyl Substituted Imidazole Sulfonamide Derivatives as Inhibitors of Transforming Growth Factor-β1 Type I Receptor
Authors
정선희
Issue Date
2005
Department/Major
대학원 약학과
Publisher
이화여자대학교 대학원
Degree
Master
Abstract
임상적으로, transforming growth factor β (TGF-β)의 병원성 작용을 제어하고 정상적인 기전에서 TGF-β의 효과를 조절하는 미세 분자에 대한 필요가 커지고 있다. TGF-β 신호전달의 억제는 피부 상처의 재구성을 촉진시키고 흉터의 섬유화를 억제할 것으로 기대할 수 있다. TGF-β 신호전달 체계의 선택적인 미세 분자 억제제들이 질병 치료를 목적으로 개발되었고 이는 또한 TGF-β의 복합적인 전달 체계, 특히 다른 신호전달 경로들과의 교차 작용을 실험적으로 상세히 분석하는데 있어 쓸모 있는 도구가 될 것이다. 이번 연구에서, 우리는 luciferase reporter assay에서 ALK5 억제 효능을 알아보기 위해 일련의 2-pyridyl이 치환된 imidazole sulfonamide 유도체들을 합성하고 평가하였다. 이 중 화합물 8b (p3TP-luciferase, 93%; SBE-luciferase, 70%; ARE-luciferase, 60%)와 8c (p3TP-luciferase, 94%; SBE-luciferase, 74%; ARE-luciferase, 62%)가 비교 화합물인 SB-431542 (p3TP-luciferase, 75%; SBE-luciferase, 53%; ARE-luciferase, 24%)와 비교하여 0.1 µM 농도에서 현저히 높은 ALK5 억제 작용을 보였다.;Clinically, there is a great need for small molecule inhibitors that could control pathogenic effects of transforming growth factor (TGF-β) and/or modulate effects of TGF-β in normal responses. 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 experimetally dissecting this complex pathway, especially its cross-talk with other signaling pathways. In this study, we synthesized and evaluated a series of 2-pyridyl substituted imidazole sulfonamide derivatives for their ALK5 inhibitory activity in the luciferase reporter assays. Compunds 8b (p3TP-luciferase, 93%; SBE-luciferase, 70%; ARE-luciferase, 60%) and 8c (p3TP-luciferase, 94%; SBE-luciferase, 74%; ARE-luciferase, 62%) showed significant ALK5 inhibition at a concentration of 0.1 µM that is higher than that of SB-431542 (p3TP-luciferase, 75%; SBE-luciferase, 53%; ARE-luciferase, 24%).
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