BACE-1 and γ-Secretase as Therapeutic Targets for Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a growing global health concern with a massive impact on affected individuals and society. Despite the considerable advances achieved in the understanding of AD pathogenesis, researchers have not been successful in fully identifying the mechanisms involved in disease progression. The amyloid hypothesis, currently the prevalent theory for AD, defends the deposition of β-amyloid protein (Aβ) aggregates as the trigger of a series of events leading to neuronal dysfunction and dementia. Hence, several research and development (R&D) programs have been led by the pharmaceutical industry in an effort to discover effective and safety anti-amyloid agents as disease modifying agents for AD. Among 19 drug candidates identified in the AD pipeline, nine have their mechanism of action centered in the activity of β or γ-secretase proteases, covering almost 50% of the identified agents. These drug candidates must fulfill the general rigid prerequisites for a drug aimed for central nervous system (CNS) penetration and selectivity toward different aspartyl proteases. This review presents the classes of γ-secretase and beta-site APP cleaving enzyme 1 (BACE-1) inhibitors under development, highlighting their structure-activity relationship, among other physical-chemistry aspects important for the successful development of new anti-AD pharmacological agents.

Keywords: Alzheimer’s disease; BACE-1; amyloid hypothesis; γ-secretase.

Figure 1

Mechanism of action of AD agents in clinical trials in 2018. Adapted from [14].

Figure 2

Cascade of events according the amyloid hypothesis. Adapted from [16].

Figure 3

Scheme of the production of Aβ by the two step sequential cleavage of APP by β-secretase and γ-secretase. Adapted from [15].

Figure 4

Crystal structure of human γ-secretase. Adapted by permission from Xiao-chen Bai et al. Nature [30], Copyright 2015.

Figure 5

Cleavage steps of C99 by GS. Adapted with permission from [17]. Copyright 2016 American Chemical Society.

Figure 6

γ-Secretase inhibitors (1–2) advanced in late-stage clinical trials.

Figure 7

NSAIDs GSMs 3–5 and respective Aβ42 half-maximal inhibitory concentration (IC₅₀) values [44].

Figure 8

Tarenflurbil (R-flurbiprofen) (6).

Figure 9

CHF5074 (7) and EVP-0015962 (8).

Figure 10

Improvement activity and selectivity of CHF5074 (7) against tarenflurbil (6).

Figure 11

Structure of NGP555 (11).

Figure 12

Structure-activity relationship (SAR) of non-NSAID GSMs four rings scaffold.

Figure 13

Examples of Eisai cinnamides.

Figure 14

Structures of E2012 (16) and E2212 (17, predicted structure).

Figure 15

Processing steps of APP by (A) BACE-1 and (B) GS. Adapted with permission from [17]. Copyright 2016 American Chemical Society.

Figure 16

Structures and activity of acyl guanidine-based BACE-1 inhibitors 18–21.

Figure 17

Optimization of 18 to 19.

Figure 18

Acyl guanidine-based BACE-1 inhibitors developed by BMS [66].

Figure 19

Chromane-based spirocyclic acyl guanidine-derived BACE-1 inhibitor 21 develop by Array BioPharma together with Genentech [67].

Figure 20

Bioisosteric replacement of the acyl guanidine moiety of compound 18.

Figure 21

Structure of the improved aminopyridine-base compound 24 developed by Wyeth.

Figure 22

Interactions of the improved aminopyridine-base compound 24 developed by Wyeth with the catalytic site of BACE-1. Adapted from [16].

Figure 23

HTS aminothiazine fragment hit 25.

Figure 24

SAR of optimized inhibitor 26 developed by Roche.

Figure 25

Oxazine-based compound 27 with a trifluoromethyl group developed by Roche.

Figure 26

Spirocyclic aminooxazoline lead compound 28.

Figure 27

Spirocyclic aminooxazoline developed by Amgen [68,71].

Figure 28

Aminothiazines 31–32 and aminooxazine 33 based compounds evaluated in clinical trials.

Figure 29

Merck’s aminoimidazole HTS hit.

Figure 30

Merck’s aminoimidazole-based inhibitors.

Figure 31

Bicyclic aminoimidazole hit compound 39.

Figure 32

Optimized aminoimidazole-based inhibitor 40 from Wyeth.

Figure 33

Aminoimidazole-based inhibitors 41–42 developed by AstraZeneca.

Figure 34

AZD3293 (LY3314814, lanabecestat, 43) from AstraZeneca.

Figure 35

Structures of iminopyrimidinone based compound 44 and verubecestat (45).

Figure 36

Iminohydantoin 46 previously developed by Merck.

Figure 37

Drug development and SAR of verubecestat (45).