1616100-64-1Relevant articles and documents
Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents
Wu, Yong-Jin,Guernon, Jason,Yang, Fukang,Snyder, Lawrence,Shi, Jianliang,McClure, Andrea,Rajamani, Ramkumar,Park, Hyunsoo,Ng, Alicia,Lewis, Hal,Chang, ChiehYing,Camac, Dan,Toyn, Jeremy H.,Ahlijanian, Michael K.,Albright, Charles F.,Macor, John E.,Thompson, Lorin A.
supporting information, p. 271 - 276 (2016/03/25)
By targeting the flap backbone of the BACE1 active site, we discovered 6-dimethylisoxazole-substituted biaryl aminothiazine 18 with 34-fold improved BACE1 inhibitory activity over the lead compound 1. The cocrystal structure of 18 bound to the active site indicated two hydrogen-bond interactions between the dimethylisoxazole and threonine 72 and glutamine 73 of the flap. Incorporation of the dimethylisoxazole substitution onto the related aminothiazine carboxamide series led to pyrazine-carboxamide 26 as a very potent BACE1 inhibitor (IC50 1 nM). This compound demonstrated robust brain Aβ reduction in rat dose-response studies. Thus, compound 26 may be useful in testing the amyloid hypothesis of Alzheimer's disease.