通过CS17919准ASK1,在小鼠模型中缓解了与脏和肝脏相关的疾病
Guoqiang Liao1,2, Qianjiao Yang3, Xuhua Mao1
1Chengdu Chipscreen Pharmaceutical Corp., Ltd., Chengdu, Sichuan, P.R. China.
Animal models and experimental medicine
|June 14, 2024
概括
一种新型的抑制剂,CS17919,向细胞亡信号调节激酶1 (ASK1) 以防止代谢损伤. 这种化合物通过减少炎症和纤维化,证明了对和肝脏疾病的治疗潜力.
科学领域:
- 药理学 药理学是指药理学的学科.
- 生物化学 生物化学
- 药用化学 医学化学
背景情况:
- 亡信号调节酶1 (ASK1) 是MAPK通路中的关键酶,调解炎症和亡等压力反应.
- 抑制ASK1激酶活性提供了在各种病理条件下对细胞损伤的保护机制.
- 代谢损伤,包括慢性病 (CKD) 和非酒精性脂肪肝炎 (NASH),是与ASK1激活相关的重大健康问题.
研究的目的:
- 设计,合成和评估一种新的选择性ASK1抑制剂,CS17919.
- 在代谢损伤的临床前模型中研究CS17919的药理作用和治疗潜力.
- 为了比较CS17919与已知ASK1抑制剂Selonsertib (GS-4997) 的疗效和安全性,
主要方法:
- 在体外验证CS17919的ASK1抑制活性.
- 在细胞系中对CS17919进行了体外安全分析,以对抗Selonsertib (GS-4997).
- 用小鼠进行的药理动力学 (PK) 研究和用CKD (UUO,DKD) 和NASH的小鼠模型进行体内疗效测试.
主要成果:
- CS17919在体外表现出与GS-4997相似的ASK1抑制,但在棕酸处理的细胞中毒性较低,保护性更强.
- CS17919表现出有利的PK特性,包括高血度.
- 在体内,CS17919改善了DKD模型中的功能和改善了质硬化症,并且与CS27109结合,改善了NASH模型中的肝炎和减少了纤维化.
结论:
- 在体外和体内,CS17919具有显著的细胞保护,抗炎和抗纤维性质.
- 这些发现表明,CS17919对与代谢相关的脏和肝脏疾病具有治疗前景.
- 需要进一步研究CS17919作为代谢障碍的治疗方法.
相关概念视频
02:43Mouse Models of Cancer Study
Mice have long served as models for studying human biology and pathology because of their phylogenetic and physiological similarity with humans. They are also easy to maintain and breed in the laboratory, and hence, many inbred strains are now available for research. Studies on mice have contributed immeasurably to our understanding of cancer biology.
The development of transgenic, knockout, and knock-in mice has led to an exponential increase in their use as model organisms in research,...
The development of transgenic, knockout, and knock-in mice has led to an exponential increase in their use as model organisms in research,...
02:43Mouse Models of Cancer Study
Mice have long served as models for studying human biology and pathology because of their phylogenetic and physiological similarity with humans. They are also easy to maintain and breed in the laboratory, and hence, many inbred strains are now available for research. Studies on mice have contributed immeasurably to our understanding of cancer biology.
The development of transgenic, knockout, and knock-in mice has led to an exponential increase in their use as model organisms in research,...
The development of transgenic, knockout, and knock-in mice has led to an exponential increase in their use as model organisms in research,...