Acylguanidine inhibitors of β-secretase: Optimization of the pyrrole ring substituents extending into the S1 and S3 substrate binding pockets

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.

Hit-to-lead optimization of a series of acyl guanidines by optimization of the interactions with the S1–S3 and S2′S2′ enzyme binding pockets led to submicromolar BACE-1 inhibitors.Figure optionsDownload as PowerPoint slide