202124-67-2Relevant articles and documents
Virtual screening and structure-based discovery of indole acylguanidines as potent β-secretase (BACE1) inhibitors
Zou, Yiquan,Li, Li,Chen, Wuyan,Chen, Tiantian,Ma, Lanping,Wang, Xin,Xiong, Bing,Xu, Yechun,Shen, Jingkang
, p. 5706 - 5722 (2013)
Proteolytic cleavage of amyloid precursor protein by β-secretase (BACE1) is a key step in generating the N-terminal of β-amyloid (Aβ), which further forms into amyloid plaques that are considered as the hallmark of Alzheimer's disease. Inhibitors of BACE1 can reduce the levels of Aβ and thus have a therapeutic potential for treating the disease. We report here the identification of a series of small molecules bearing an indole acylguanidine core structure as potent BACE1 inhibitors. The initial weak fragment was discovered by virtual screening, and followed with a hit-to-lead optimization. With the aid of co-crystal structures of two discovered inhibitors (compounds 19 and 25) with BACE1, we explored the SAR around the indole and aryl groups, and obtained several BACE1 inhibitors about 1,000-fold more potent than the initial fragment hit. Accompanying the lead optimization, a previously under-explored sub-site opposite the flap loop was redefined as a potential binding site for later BACE1 inhibitor design.
Design and synthesis of potent and selective 5,6-fused heterocyclic thrombin inhibitors
Dominguez, Celia,Duffy, Daniel E.,Han, Qi,Alexander, Richard S.,Galemmo Jr., Robert A.,Park, Jeongsook M.,Wong, Pancras C.,Amparo, Eugene C.,Knabb, Robert M.,Luettgen, Joseph,Wexler, Ruth R.
, p. 925 - 930 (2007/10/03)
Thrombin, a serine protease, plays a central role in the initiation of thrombotic events. We report design, synthesis, and antithrombotic efficacy of XU817 (7), a nonpeptide 5-(amidino) indole thrombin inhibitor. Utilizing the co-crystal structure of XU817 bound in the active site of thrombin we were able to synthesize analogs with enhanced thrombin affinity.
