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.

Is Alzheimer’s Disease a Liver Disease of the Brain?

“…The property of a therapeutic agent in AD to penetrate the BBB has generally been regarded as a prerequisite for new drugs [96]. Recognition of the importance of the liver in A␤ production and clearance means that targeting the liver might be a promising therapeutic approach.…”

One Pot Synthesis of Micromolar BACE-1 Inhibitors Based on the Dihydropyrimidinone Scaffold and Their Thia and Imino Analogues

“…Nanomolar inhibitors based on several heterocyclic scaffolds have been developed and a number have progressed to clinical trials [ 17 , 18 , 26 ]. Although some programs have been discontinued due to phase III failure, interest in BACE-1 inhibitors is still high, in particular for the development of modifying therapies for early stage AD [ 27 , 28 ].…”

Discovery of Sulforaphane as a Potent BACE1 Inhibitor Based on Kinetics and Computational Studies

“…With aspartic proteases being found in nearly all body tissues and involved in various physiological functions, off-target activity causing severe side effects is possible and likely if an inhibitor is not specific to BACE1 [ 19 ]. LY2811376, a promising clinical candidate of BACE1 inhibitor (IC 50 , 0.24 μM), did not proceed to phase II clinical trials because of its off-target activity against cathepsin D [ 20 ]. The present results clearly suggest that our compound only suppressed specific targeted enzyme BACE1 without causing adverse effects.…”