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.
Highlights
Following the amyloid hypothesis, where a high brain Aβ level is observed as an important factor in Alzheimer’s disease (AD) pathogenesis, pharmacological intervention to reduce its production or improve the clearance has become a logical approach for AD therapy development
The physical chemistry characteristics needed for this PK properties need to be balanced with target requirements, in which the improvements of these properties sometimes lead to a reduction on binding affinity and potency
Taking into consideration the actual AD pipeline, a special focus has been given to beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE-1) as a target for a disease modifying therapy for AD
Summary
AD is recognized by the World Health Organization (WHO) as a global public health priority [1]. In the United States of America (USA), the total annual payments for health care, long-term care and hospice care for people with AD or other dementias are projected to increase from $259 billion in 2017 to more than $1.1 trillion in 2050 [5]. These numbers show the dramatic impact that AD and the other dementias will have in the health care systems in the future. Alzheimer’s disease (fAD) mutations are involved in either AΆ increase generation or processing and Pharmaceuticals 2019, 12, 41 result in relative overproduction of toxic forms of Aβ, namely Aβ42 [3]. There are further questions concerning the exact neuronal toxicity of Aβ, the amyloid hypothesis is still broadly accepted as the general pathological cascade of events in AD [22,23]
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