194163-05-8Relevant articles and documents
Discovery of a tricyclic farnesoid X receptor agonist HEC96719, a clinical candidate for treatment of non-alcoholic steatohepatitis
Cao, Shengtian,Yang, Xinye,Zhang, Zheng,Wu, Junwen,Chi, Bo,Chen, Hong,Yu, Jianghong,Feng, Shanshan,Xu, Yulin,Li, Jing,Zhang, Yingjun,Wang, Xiaojun,Wang, Yan
supporting information, (2022/01/24)
Non-alcoholic fatty liver disease (NAFLD) is becoming the most predominant burden of chronic liver disease worldwide. Non-alcoholic steatohepatitis (NASH), the progressive form of NAFLD, can develop into cirrhosis and hepatocellular cancer. Unfortunately, current options for therapeutic treatment of NASH are very limited. Among multiple pathways in NASH, farnesoid X receptor (FXR), a nuclear bile acid receptor, is well-recognized as an important effective target. Here we report the synthesis and characterization of compound HEC96719 a novel tricyclic FXR agonist based on a prior high-affinity nonsteroidal molecule GW4064. HEC96719 exhibits excellent potency superior to GW4064 and obeticholic acid in in vitro and in vivo assays of FXR activation. It also shows higher FXR selectivity and more favorable tissue distribution dominantly in liver and intestine. Preclinical data on pharmacokinetic properties, efficacy, and safety profiles overall indicate that HEC96719 is a promising drug candidate for NASH treatment.
Use of conformationally restricted benzamidines as arginine surrogates in the design of platelet GPIIb-IIIa receptor antagonists
Sall, Daniel J.,Arfsten, Ann E.,Bastian, Jolie A.,Denney, Michael L.,Harms, Cathy S.,McCowan, Jefferson R.,Morin Jr., John M.,Rose, Jack W.,Scarborough, Robert M.,Smyth, Mark S.,Um, Suzane L.,Utterback, Barbara G.,Vasileff, Robert T.,Wikel, James H.,Wyss, Virginia L.,Jakubowski, Joseph A.
, p. 2843 - 2857 (2007/10/03)
The use of 5,6-bicyclic amidines as arginine surrogates in the design of a novel class of potent platelet glycoprotein IIb-IIIa receptor (GPIIb-IIIa) antagonists is described. The additional conformational restriction offered by the bicyclic nucleus results in 20-400-fold increases in potency compared to the freely flexible, acyclic benzamidine counterpart. The design, synthesis, structure-activity relationships (SAR), and in vitro activity of this novel class of GPIIb-IIIa antagonists are presented.
