Discovery of 7-Tetrahydropyran-2-yl Chromans: β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors That Reduce Amyloid β-Protein (Aβ) in the Central Nervous System

Thomas, Allen A.; Hunt, Kevin W.; Volgraf, Matthew; Watts, Ryan J.; Liu, Xingrong; Vigers, Guy; Smith, Dena M.; Sammond, Douglas M.; Tang, Tony P.; Rhodes, Susan P.; Metcalf, Andrew T.; Brown, Karin D.; Otten, Jennifer; Burkard, Michael; Cox, April; Geck, Mary; Dutcher, Darrin; Rana, Sumeet; DeLisle, Robert Kirk; Regal, Kelly; Wright, Albion D.; Groneberg, Robert D.; Scearce‐Levie, Kimberly; Siu, Michael; Purkey, Hans E.; Lyssikatos, Joseph P.; Gunawardana, Indrani

doi:10.1021/jm401635n

Cited by 38 publications

(11 citation statements)

References 55 publications

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“…Array BioPharma together with Genentech developed a series of chromane-based spirocyclic acyl guanidine-derived BACE-1 inhibitors leading to compound 21 (Figure 19). Although it showed a good selectivity to BACE-1 and was able to reduce CSF Aβ40 levels from 53% to 63% in rat and cyno, respectively, this compound also showed a high efflux ratio by P-gp [67].…”

Section: Amyloid Targeting Strategiesmentioning

confidence: 99%

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

Maia

Sousa

2019

Pharmaceuticals

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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.

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Section: Amyloid Targeting Strategiesmentioning

confidence: 99%

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

Section: Figurementioning

confidence: 99%

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

Maia

Sousa

2019

Pharmaceuticals

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“…Additionally, this compound also had the ability to decrease the levels of Aβ40 in CSF from 53% to 63% in rats and cynomolgus monkeys, respectively. Furthermore, this compound exhibited a high efflux ratio of P-gp [108].…”

Section: Anti-alzheimer's Molecules Targeting β-Secretasementioning

confidence: 95%

Novel Anti-Alzheimer’s Therapeutic Molecules Targeting Amyloid Precursor Protein Processing

Uddin

Kabir

Jeandet

et al. 2020

Oxidative Medicine and Cellular Longevity

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Alzheimer’s disease (AD) is the most common cause of dementia among older people, and the prevalence of this disease is estimated to rise quickly in the upcoming years. Unfortunately, almost all of the drug candidates tested for AD until now have failed to exhibit any efficacy. Henceforth, there is an increased necessity to avert and/or slow down the advancement of AD. It is known that one of the major pathological characteristics of AD is the presence of senile plaques (SPs) in the brain. These SPs are composed of aggregated amyloid beta (Aβ), derived from the amyloid precursor protein (APP). Pharmaceutical companies have conducted a number of studies in order to identify safe and effective anti-Aβ drugs to combat AD. It is known that α-, β-, and γ-secretases are the three proteases that are involved in APP processing. Furthermore, there is a growing interest in these proteases, as they have a contribution to the modulation and production of Aβ. It has been observed that small compounds can be used to target these important proteases. Indeed, these compounds must satisfy the common strict requirements of a drug candidate targeted for brain penetration and selectivity toward different proteases. In this article, we have focused on the auspicious molecules which are under development for targeting APP-processing enzymes. We have also presented several anti-AD molecules targeting Aβ accumulation and phosphorylation signaling in APP processing. This review highlights the structure-activity relationship and other physicochemical features of several pharmacological candidates in order to successfully develop new anti-AD drugs.

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“…Using structure-based design these chemotypes were substituted with three different aspartate-binding groups: aminohydantoin, aminooxazolines, and aminothiazolines, in an attempt to modulate potency, selectivity, efflux, and permeability. In the first chemotype, the aminohydantoin analogs were the most potent and selective against Cathepsin-D (Thomas et al, 2014a , b ).…”

Section: Challenges In Bace1 Inhibitor Developmentmentioning

confidence: 99%

Highlights in BACE1 Inhibitors for Alzheimer's Disease Treatment

et al. 2018

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Alzheimer's disease (AD) is a severe neurodegenerative disorder and the most common type of dementia in the elderly. The clinical symptoms of AD include a progressive loss of memory and impairment of cognitive functions interfering with daily life activities. The main neuropathological features consist in extracellular amyloid-β (Aβ) plaque deposition and intracellular Neurofibrillary tangles (NFTs) of hyperphosphorylated Tau. Understanding the pathophysiological mechanisms that underlie neurodegeneration in AD is essential for rational design of neuroprotective agents able to prevent disease progression. According to the “Amyloid Cascade Hypothesis” the critical molecular event in the pathogenesis of AD is the accumulation of Aβ neurotoxic oligomers. Since the proteolytic processing of Amyloid Precursor Protein (APP) by β-secretase (beta-site APP cleaving enzyme 1, BACE1) is the rate-limiting step in the production of Aβ, this enzyme is considered a major therapeutic target and BACE1 inhibitors have the potential to be disease-modifying drugs for AD treatment. Therefore, intensive efforts to discover and develop inhibitors that can reach the brain and effectively inhibit BACE1 have been pursued by several groups worldwide. The aim of this review is to highlight the progress in the discovery of potent and selective small molecule BACE1 inhibitors over the past decade.

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Discovery of 7-Tetrahydropyran-2-yl Chromans: β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors That Reduce Amyloid β-Protein (Aβ) in the Central Nervous System

Cited by 38 publications

References 55 publications

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

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

Novel Anti-Alzheimer’s Therapeutic Molecules Targeting Amyloid Precursor Protein Processing

Highlights in BACE1 Inhibitors for Alzheimer's Disease Treatment

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