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.
Indolyl and dihydroindolyl N-glycinamides as potent and in vivo active NPY5 antagonists
Wu, Lingyun,Lu, Kai,Packiarajan, Mathivanan,Jubian, Vrej,Chandrasena, Gamini,Wolinsky, Toni C.,Walker, Mary W.
scheme or table, p. 2167 - 2171 (2012/04/18)
A novel series of indolyl and dihydroindolyl glycinamides were identified as potent NPY5 antagonists with in vivo activity from screen hit 1. The dihydroindolyl glycinamide 10a significantly inhibits NPY5 agonist induced feeding at a dose of 0.1 mg/kg. The indolyl glycinamide 12c also inhibits NPY5 agonist induced feeding at a dose of 1 mg/kg. Both compounds 10a and 12c represent potential tools for further investigation into the biology of the NPY5 receptor.
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.
