Piperazine sulfonamide BACE1 inhibitors: Design, synthesis, and in vivo characterization

Cumming, Jared N.; Babu, Suresh; Huang, Ying; Carrol, Carolyn; Chen, Xia; Favreau, Leonard; Greenlee, William J.; Guo, Tao; Kennedy, Matthew; Kuvelkar, Reshma; Le, Thuy X.; Li, Guoqing; McHugh, Nansie A.; Orth, Peter; Ozgur, Lynne; Parker, Eric M.; Saionz, Kurt W.; Stamford, Andrew W.; Strickland, Corey; Tadesse, Dawit; Voigt, Johannes H.; Zhang, Lili; Zhang, Qi

doi:10.1016/j.bmcl.2010.03.050

Cited by 44 publications

(18 citation statements)

References 39 publications

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“…Preliminary analyses in our laboratory strongly suggest that thalidomide-induced decrease in amyloid loads is associated with significantly lower brain BACE1 levels (unpublished observations), though it is not clear yet whether the drug directly affects BACE1 or whether the effect is secondary to reduced inflammation. Finally, while most laboratories aim at developing small molecule BACE1 inhibitors that can cross the BBB, some larger compounds that do not cross the BBB were also shown to be effective in reducing brain Aβ levels in rodent models [162]. However, once we confirm our pre-clinical data, one could suggest testing thalidomide analogs displaying better tolerability in humans.…”

Section: Alternative Strategiessupporting

confidence: 53%

BACE1 Inhibitors: Attractive Therapeutics for Alzheimer’s Disease

Decourt

Macias

Sabbagh

et al. 2014

Drug Design and Discovery in Alzheimer's Disease

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Section: Alternative Strategiessupporting

confidence: 53%

BACE1 Inhibitors: Attractive Therapeutics for Alzheimer’s Disease

Decourt

Macias

Sabbagh

et al. 2014

Drug Design and Discovery in Alzheimer's Disease

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“…6, K i = 0.18 nM, cell IC 50 = 7 nM) which induced a robust and persistent lowering of peripheral Aβ in a transgenic mouse model following a single subcutaneous dose. However, P-gp liability limited its central efficacy [68]. …”

Section: Bioisosteric Morphing Of Early Transition State Isostere-mentioning

confidence: 99%

The Structural Evolution of β-Secretase Inhibitors: A Focus on the Development of Small-Molecule Inhibitors

Butini¹,

Brogi²,

Novellino³

et al. 2013

CTMC

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Effective treatment of Alzheimer’s disease (AD) remains a critical unmet need in medicine. The lack of useful treatment for AD led to an intense search for novel therapies based on the amyloid hypothesis, which states that amyloid β-42 (Aβ42) plays an early and crucial role in all cases of AD. β-Secretase (also known as BACE-1 β-site APP-cleaving enzyme, Asp-2 or memapsin-2) is an aspartyl protease representing the rate limiting step in the generation of Aβ peptide fragments, therefore it could represent an important target in the steady hunt for a disease-modifying treatment. Generally, β-secretase inhibitors are grouped into two families: peptidomimetic and nonpeptidomimetic inhibitors. However, irrespective of the class, serious challenges with respect to blood–brain barrier (BBB) penetration and selectivity still remain. Discovering a small molecule inhibitor of β-secretase represents an unnerving challenge but, due to its significant potential as a therapeutic target, growing efforts in this task are evident from both academic and industrial laboratories. In this frame, the rising availability of crystal structures of β-secretase-inhibitor complexes represents an invaluable opportunity for optimization. Nevertheless, beyond the inhibitory activity, the major issue of the current research approaches is about problems associated with BBB penetration and pharmacokinetic properties. This review follows the structural evolution of the early β-secretase inhibitors and gives a snap-shot of the hottest chemical templates in the literature of the last five years, showing research progress in this field.

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“…Initial hit finding strategies uncovered potent BACE1 inhibitors which were all P-glycoprotein efflux substrates (15). A subsequent fragment screen using heteronuclear single quantum coherence (HSQC) NMR screening of 15 N-BACE1 on 10,000 compounds at 500 μM in pools of 10 successfully identified a new chemical series (16).…”

Section: Bace Inhibition -A Tough Target Starts To Yieldmentioning

confidence: 99%

Alzheimer's disease therapeutics - Are we winning or losing? Highlights from the Society for Medicines Research Symposium, held on March 16, 2012, Brussels, Belgium

Davenport¹,

Karran²,

MacDonald³

et al. 2012

Drugs Fut

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Piperazine sulfonamide BACE1 inhibitors: Design, synthesis, and in vivo characterization

Cited by 44 publications

References 39 publications

BACE1 Inhibitors: Attractive Therapeutics for Alzheimer’s Disease

BACE1 Inhibitors: Attractive Therapeutics for Alzheimer’s Disease

The Structural Evolution of β-Secretase Inhibitors: A Focus on the Development of Small-Molecule Inhibitors

Alzheimer's disease therapeutics - Are we winning or losing? Highlights from the Society for Medicines Research Symposium, held on March 16, 2012, Brussels, Belgium

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Piperazine sulfonamide BACE1 inhibitors: Design, synthesis, and in vivo characterization

Cited by 44 publications

References 39 publications

BACE1 Inhibitors: Attractive Therapeutics for Alzheimer’s Disease

BACE1 Inhibitors: Attractive Therapeutics for Alzheimer’s Disease

The Structural Evolution of &#946;-Secretase Inhibitors: A Focus on the Development of Small-Molecule Inhibitors

Alzheimer's disease therapeutics - Are we winning or losing? Highlights from the Society for Medicines Research Symposium, held on March 16, 2012, Brussels, Belgium

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Product

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The Structural Evolution of β-Secretase Inhibitors: A Focus on the Development of Small-Molecule Inhibitors