The evolution of amidine-based brain penetrant BACE1 inhibitors

Abstract

Beta site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors hold great potential as disease modifying anti-Alzheimer's drugs. This digest provides an overview of the amidine containing class of BACE1 inhibitors, of which multiple examples are now progressing through clinical trials. The various structural modifications highlight the struggle to combine potency with the optimal properties for a brain penetrant BACE1 inhibitor, and illustrate the crowded competitive landscape. This overview concludes with a summary of potential issues including substrate and target selectivity and a synopsis of the status of the current and past clinical assets.

Structure-based optimization of non-peptidic Cathepsin D inhibitors

“…A meaningful cyclization of the acylguanidine might result in heterocycles maintaining the crucial H-bond interactions to the catalytic aspartates, but with favourable pharmacokinetic properties as shown for BACE1. 34 …”

Preparation and biological evaluation of conformationally constrained BACE1 inhibitors

“…[1][2][3][4][5] Owing to its critical role in the production of Ab, BACE1 has been aggressively pursued as a key target for development of a potential Alzheimer's disease therapy. [6][7][8] We have previously reported on the fragment-based discovery of LY2811376 (1, Fig. 1), the first molecule reported to demonstrate robust reduction of human CSF Ab in a Phase I clinical trial.…”

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.…”