905966-60-1Relevant articles and documents
Acylguanidine inhibitors of β-secretase: Optimization of the pyrrole ring substituents extending into the S1 and S3 substrate binding pockets
Cole, Derek C.,Stock, Joseph R.,Chopra, Rajiv,Cowling, Rebecca,Ellingboe, John W.,Fan, Kristi Y.,Harrison, Boyd L.,Hu, Yun,Jacobsen, Steve,Jennings, Lee D.,Jin, Guixian,Lohse, Peter A.,Malamas, Michael S.,Manas, Eric S.,Moore, William J.,O'Donnell, Mary-Margaret,Olland, Andrea M.,Robichaud, Albert J.,Svenson, Kristine,Wu, JunJun,Wagner, Eric,Bard, Jonathan
, p. 1063 - 1066 (2008/09/19)
Proteolytic cleavage of amyloid precursor protein by β-secretase (BACE-1) and γ-secretase leads to formation of β-amyloid (Aβ) a key component of amyloid plaques, which are considered the hallmark of Alzheimer's disease. Small molecule inhibitors of BACE-1 may reduce levels of Aβ and thus have therapeutic potential for treating Alzheimer's disease. We recently reported the identification of a novel small molecule BACE-1 inhibitor N-[2-(2,5-diphenyl-pyrrol-1-yl)-acetyl]guanidine (3.a.1). We report here the initial hit-to-lead optimization of this hit and the SAR around the aryl groups occupying the S1 and S2′ pockets leading to submicromolar BACE-1 inhibitors.
