Synthesis, SAR, and X-ray structure of human BACE-1 inhibitors with cyclic urea derivatives

Park, Heuisul; Min, Kyung Soo; Kwak, Hyo-Shin; Koo, Ki Dong; Lim, Dongchul; Seo, Sachiko; Choi, Jae-Ung; Platt, Bettina; Choi, Deog-Young

doi:10.1016/j.bmcl.2008.03.081

Cited by 22 publications

(5 citation statements)

References 11 publications

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“…A series of compounds with phenethyl in the P2 position, lactam ring in the P3 position, and pyrrolidine ring containing the essential basic amine yielded potent compounds, with compound 20 exhibiting cell activity of 0.005 μM and Aβ lowering in the brains of P-gp deficient (MDR1a–/−) mice . The majority of the compounds in this series exhibited good potency but suffered from lack of efficacy in mice with the compound level in the brain 3-fold over the cell IC 50 . , …”

Section: Bace1 Inhibitor Designmentioning

confidence: 98%

“…106 The majority of the compounds in this series exhibited good potency but suffered from lack of efficacy in mice with the compound level in the brain 3-fold over the cell IC 50 . 107,108 A novel functional group interacting with the catalytic center, similar to the one developed for HIV1 protease inhibitors, contains the key hydroxyl and amine functionalities grafted onto a six-membered cyclic sulfone ring. Compound 21 (PDB code 3QBH) exhibits moderate activity of 0.15 μM against the enzyme with no permeability into the CNS.…”

Section: Hydroxyethylamines (Hea)mentioning

confidence: 99%

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Structure-Based Design of β-Site APP Cleaving Enzyme 1 (BACE1) Inhibitors for the Treatment of Alzheimer’s Disease

Yuan¹,

Shankar²,

Zheng³

et al. 2013

J. Med. Chem.

128

134

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The amyloid hypothesis asserts that excess production or reduced clearance of the amyloid-β (Aβ) peptides in the brain initiates a sequence of events that ultimately lead to Alzheimer's disease and dementia. The Aβ hypothesis has identified BACE1 as a therapeutic target to treat Alzheimer's and led to medicinal chemistry efforts to design its inhibitors both in the pharmaceutical industry and in academia. This review summarizes two distinct categories of inhibitors designed based on conformational states of "closed" and "open" forms of the enzyme. In each category the inhibitors are classified based on the core catalytic interaction group or the aspartyl binding motif (ABM). This review covers the description of inhibitors in each ABM class with X-ray crystal structures of key compounds, their binding modes, related structure-activity data highlighting potency advances, and additional properties such as selectivity profile, P-gp efflux, pharmacokinetic, and pharmacodynamic data.

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Section: Bace1 Inhibitor Designmentioning

confidence: 98%

Section: Hydroxyethylamines (Hea)mentioning

confidence: 99%

Structure-Based Design of β-Site APP Cleaving Enzyme 1 (BACE1) Inhibitors for the Treatment of Alzheimer’s Disease

Yuan¹,

Shankar²,

Zheng³

et al. 2013

J. Med. Chem.

128

134

View full text Add to dashboard Cite

show abstract

“…BACE-1 is a type-1 membrane-anchored aspartyl protease responsible for the first step of the proteolysis of APP, identified in 1999 [61]. BACE-1 cleaves APP in the luminal surface of the plasma membrane and releases the soluble ectodomain of APP, leaving C99 (Aβ plus AICD) in the membrane to be subsequently cleaved by GS to generate Aβ peptides of different lengths as previously described (Figure 15) [61,62].…”

Section: Amyloid Targeting Strategiesmentioning

confidence: 99%

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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“…Several examples are shown in Figure 10. These can be roughly classified by their transition state mimic and include: (1) peptidomimetic designs incorporating statine Hu et al, 2003Hu et al, , 2004Lamar et al, 2004;Tung et al, 2002], hydroxymethylcarbonyl [Hamada et al, 2006[Hamada et al, , 2008aShuto et al, 2003], or hydroxyethylene [Brady et al, 2004;Ghosh et al, 2006;Hanessian et al, 2005;Hom et al, 2004;Xiao et al, 2006]; (2) nonpeptidic designs incorporating a reduced amide , hydroxymethylcarbonyl [Hamada et al, 2008a,b] hydroxyethylene [Ghosh et al, 2007], hydroxyethylamine Freskos et al, 2007a,b;Ghosh et al, 2008;Kortum et al, 2007;Maillard et al, 2007;Park et al, 2008;Stachel et al, 2004Stachel et al, , 2006Stauffer et al, 2007], aminoethylene , or tertiary carbinamine [Lindsley et al, 2007;Rajapakse et al, 2006]; (3) arylpiperazines [Garino et al, 2006]; (4) acylguanidines Fobare et al, 2007;Jennings et al, 2008]; (5) dihydroquinazolines [Baxter et al, 2007]; (6) isocytosines Geschwindner et al, 2007]; (7) pyrrolidine/piperidines [Iserloh et al,Fig. 9.…”

Section: Structure-based Designmentioning

confidence: 99%

Structure and modeling in the design of β‐ and γ‐secretase inhibitors

Holloway

Hunt

McGaughey

2009

Drug Development Research

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This review discusses the involvement of structure and modeling in the design of b-secretase (BACE-1) and g-secretase inhibitors as putative Alzheimer's Disease therapeutics. The early and broad availability of structural information for BACE-1, a membrane-tethered aspartyl protease, has led to the use of in silico methods in the overall design and optimization process. However, for g-secretase, an integral membrane protein, the lack of a detailed 3D structure has limited the application of computational methods. Drug Dev Res 70 : 70-93, 2009.

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Synthesis, SAR, and X-ray structure of human BACE-1 inhibitors with cyclic urea derivatives

Cited by 22 publications

References 11 publications

Structure-Based Design of β-Site APP Cleaving Enzyme 1 (BACE1) Inhibitors for the Treatment of Alzheimer’s Disease

Structure-Based Design of β-Site APP Cleaving Enzyme 1 (BACE1) Inhibitors for the Treatment of Alzheimer’s Disease

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

Structure and modeling in the design of β‐ and γ‐secretase inhibitors

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