BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease

Abstract

BACE1 (β-secretase, memapsin 2, Asp2) has emerged as a promising target for the treatment of Alzheimer's Disease. BACE1 is an aspartic protease which functions in the first step of the pathway leading to the production and deposition of amyloid-β peptide (Aβ). Its gene deletion showed only mild phenotypes. BACE1 inhibition has direct implications in the Alzheimer's Disease pathology without largely affecting viability. However, inhibiting BACE1 selectively in vivo has presented many challenges to medicinal chemists. Since its identification in 2000, inhibitors covering many different structural classes have been designed and developed. These inhibitors can be largely classified as either peptidomimetic or non-peptidic inhibitors. Progress in these fields resulted in inhibitors that contain many targeted drug-like characteristics. In this review, we describe structure-based design strategies and evolution of a wide range of BACE1 inhibitors including compounds that have been shown to reduce brain Aβ, rescue the cognitive decline in transgenic AD mice and inhibitor drug candidates that are currently in clinical trials.

Reducing Aβ load and tau phosphorylation: Emerging perspective for treating Alzheimer's disease

“…In general, it can also be said that β-site APP cleaving enzyme (BACE-1), promotes amyloidogenic pathway. BACE1 is an aspartic protease, which functions in the first step of the pathway leading to the production and deposition of Aβ and inhibition of this enzyme is implicated in AD pathology without largely affecting viability (Ghosh and Osswal, 2014).…”

Design, synthesis and biological evaluation of tasiamide B derivatives as BACE1 inhibitors

“…[10][11][12][13][14] Over the past decade, a large number of peptidic and pseudopeptidic BACE1 inhibitors have been reported. [15][16][17][18][19][20][21][22][23][24][25] Most of these inhibitors comprised a statine (c-amino-b-hydroxy acid) residue, which formed hydrogen bonding interactions with two aspartic acids in the catalytic site. Tang and coworkers described the X-ray crystal structure of a large peptidic inhibitor OM99-2 (K i = 1.6 nM, Fig.…”

Evaluation of transition-state mimics in a superior BACE1 cleavage sequence as peptide-mimetic BACE1 inhibitors

“…Thus, an inhibitor of BACE1 would prevent A production at the initial processing step, and could be a promising anti-AD drug [2][3][4][5][6][7][8] . Inhibition of BACE1 is expected to be clinically feasible, since BACE1 null mice proved viable with few phenotypical abnormalities.…”

“…Hz, 2H), 7.61 (t, J = 7.0 Hz, 2H), 7.37-7.14 (m, 9H), 6.38 (brd, J = 9 2. Hz, 1H), 4.31-4.29 (m, 1H), 4.21-4.10 (m, 4H), 2.99 (dd, J = 13.2, 7.6 Hz, 1H), 2.89 (dd, J = 13.2, 7.6 Hz, 1H), 2.03-1.99 (m, 1H); 13 C NMR (100 MHz, CD 3 COCD 3 ):  = 174.0, 156.1, 144.53, 144.47, 141.5, 138.9, 129.7, 128.7, 127.9, 127.42, 127.38, 126.6, 125.7, 120.2, 70.8, 66.6, 55.8, 47.4, 38.1; HRMS (FAB) Calcd.…”