(S)-N-(5-Chlorothiophene-2-sulfonyl)-beta,beta-diethylalaninol a Notch-1-sparing gamma-secretase inhibitor.

@article{Cole2009SN5Chlorothiophene2sulfonylbetabetadi,
  title={(S)-N-(5-Chlorothiophene-2-sulfonyl)-beta,beta-diethylalaninol a Notch-1-sparing gamma-secretase inhibitor.},
  author={Derek Cecil Cole and Joseph Raymond Stock and Anthony F. Kreft and Madelene Miyoko Antane and Suzan H Aschmies and Kevin P. Atchison and David S. Casebier and Thomas A. Comery and George Diamantidis and John Watson Ellingboe and Boyd Lynn Harrison and Yun Hu and Mei Jin and Dennis M. Kubrak and Peimin Lu and Charles William Mann and Robert L. Martone and William J. Moore and Aram Oganesian and David R. Riddell and June Sonnenberg-Reines and Shaiu-Ching Sun and Erik Wagner and Zheng Wang and Kevin R. Woller and Zheng Xu and Hua Zhou and Jack Steven Jacobsen},
  journal={Bioorganic \& medicinal chemistry letters},
  year={2009},
  volume={19 3},
  pages={
          926-9
        }
}
Accumulation of beta-amyloid (Abeta), produced by the proteolytic cleavage of amyloid precursor protein (APP) by beta- and gamma-secretase, is widely believed to be associated with Alzheimer's disease (AD). Research around the high-throughput screening hit (S)-4-chlorophenylsulfonyl isoleucinol led to the identification of the Notch-1-sparing (9.5-fold) gamma-secretase inhibitor (S)-N-(5-chlorothiophene-2-sulfonyl)-beta,beta-diethylalaninol 7.b.2 (Abeta(40/42) EC(50)=28 nM), which is… Expand
A facile enantioselective synthesis of (S)-N-(5-chlorothiophene-2-sulfonyl)-β,β-diethylalaninol via proline-catalyzed asymmetric α-aminooxylation and α-amination of aldehyde
Abstract A high-yielding enantioselective synthesis of the bioactive (S)-N-(5-chlorothiophene-2-sulfonyl)-β,β-diethylalaninol (1), a Notch-1-sparing γ-secretase inhibitor metabolite (with EC50 = 28Expand
Synthesis and structure-activity relationship of a novel series of heterocyclic sulfonamide gamma-secretase inhibitors.
TLDR
A novel series of heterocyclic sulfonamide gamma-secretase inhibitors that reduce beta-amyloid levels in cells is reported, and several examples of compounds demonstrate a higher propensity to inhibit the processing of amyloid precursor protein compared to Notch, an alternative gamma- secretase substrate. Expand
Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease
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The discovery of ELN475516 demonstrates that it is possible to develop APP selective gamma-secretase inhibitors with potential for treatment for AD, and shows that the potency of gamma- secretase inhibitors in AD transgenic mice should be corroborated in wild-type mice. Expand
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Detailed in vitro and in vivo profiling reveal that the sulfonimidamide motif imparts desirable properties such as decreased lipophilicity and plasma protein binding, accompanied by increased solubility, which support a wider use of this unique functional group in the design of new pharmacologically active agents. Expand
Generation of Amyloid‐β Peptides by γ‐Secretase
γ-Secretase is a four-component membrane-embedded aspartyl protease involved in the final cleavage step of the amyloid precursor protein (APP) to generate the amyloid-β (Aβ) peptide. DifferentExpand
BACE and γ-Secretase Characterization and Their Sorting as Therapeutic Targets to Reduce Amyloidogenesis
TLDR
New developments the authors highlight include an important role for an ‘early recycling endosome’ coated in retromercomplex containing lipoprotein receptor LRP-II (SorLA) for switching APP to a non-amyloidogenic pathway for α-secretases processing, or to shuttleAPP to a ‘lateendosome compartment’ to form Aβ or AICD. Expand
An Overview of APP Processing Enzymes and Products
TLDR
A concise description of the current state of understanding the enzymes involved in APP processing, the cleavage products generated by different processing patterns, and the potential functions of those Cleavage products is provided. Expand
An APP inhibitory domain containing the Flemish mutation residue modulates γ-secretase activity for Aβ production
TLDR
This mode of regulation represents an unprecedented mechanism for modulating γ-secretase, providing insight into the molecular basis of Alzheimer's disease pathogenesis and a potential strategy for the development of therapeutics. Expand
γ-Secretase and its modulators: Twenty years and beyond
  • W. Xia
  • Medicine
  • Neuroscience Letters
  • 2019
TLDR
While a lack of complete understanding of presenilin biology renders failure of clinical trials, the lessons learned from some γ-secretase modulators, while premature for human testing, provide new directions to develop potential therapeutics. Expand
Pharmacological Analysis of Drosophila melanogaster γ-Secretase with Respect to Differential Proteolysis of Notch and APP
TLDR
Examination of the dose-response effects of several inhibitors on Notch and APP in Drosophila melanogaster cells indicates that despite an overall conservation in inhibitor potencies toward different γ-secretase substrates, quantitative differences might exist that could be relevant for the development of therapeutically valuable substrate-specific inhibitors. Expand
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References

SHOWING 1-10 OF 12 REFERENCES
Efficient method for the total asymmetric synthesis of the isomers of β-methyltyrosine
α-Amino acids modified at the β-carbon atom can provide topographical constraints when incorporated into a peptide. Such modifications can modulate the physical, chemical, and biological propertiesExpand
Dynamics of β-Amyloid Reductions in Brain, Cerebrospinal Fluid, and Plasma of β-Amyloid Precursor Protein Transgenic Mice Treated with a γ-Secretase Inhibitor
TLDR
It is possible for γ-secretase inhibitors to reduce brain Aβ without causing Notch-mediated toxicity, and no changes in the maturation of CD8+ thymocytes or of intestinal goblet cells were observed in mice treated with BMS-299897. Expand
High throughput screens for the identification of compounds that alter the accumulation of the Alzheimer's amyloid β peptide (Aβ)
TLDR
To screen for compounds that affect Aβ levels, a high throughput, cell-based assays capable of the and selective detection of Aβ40 in parallel with the more amyloidogenic form of the peptide, Aβ42 are established. Expand
Progress toward a practical BACE-1 inhibitor.
TLDR
This review will summarize the recent development of BACE-1 inhibitors with particular focus placed on inhibitors that address some of the requirements necessary for a practical drug candidate. Expand
Safety, Tolerability, and Changes in Amyloid β Concentrations After Administration of a γ-Secretase Inhibitor in Volunteers
TLDR
A dose-dependent reduction in plasma Aβ was demonstrated, and changes in Plasma Aβ concentrations were temporally related to the pharmacokinetic characteristics of LY450139. Expand
Effects of a γ-secretase inhibitor in a randomized study of patients with Alzheimer disease
TLDR
LY450139 dihydrate, a γ-secretase inhibitor, was studied in a randomized, controlled trial of 70 patients with Alzheimer disease and found it to be a well tolerated treatment. Expand
Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation.
  • J. Milano, J. McKay, +7 authors P. Ciaccio
  • Medicine, Biology
  • Toxicological sciences : an official journal of the Society of Toxicology
  • 2004
TLDR
Western blotting of fecal protein from BZ-and DBZ-dosed animals exhibited increased levels of both anti-Rath1 reactive protein and anti-adipsin reactive proteins, confirming their potential value as noninvasive biomarkers of intestinal goblet metaplasia. Expand
Progress toward the discovery and development of efficacious BACE inhibitors.
TLDR
The recent literature relating to the discovery and development of efficacious BACE inhibitors is reviewed with particular emphasis on the patent literature. Expand
Shedding and γ-secretase-mediated intramembrane proteolysis of the mucin-type molecule CD43
TLDR
A novel way to explain how mucin-type molecules may transduce intracellular signals can be proposed. Expand
Disease modifying strategies for the treatment of Alzheimer's disease targeted at modulating levels of the beta-amyloid peptide.
TLDR
A variety of approaches and mechanisms capable of modulating levels of Abeta are reviewed, which are of significant interest with regard to identifying novel disease modifying therapies for the treatment of AD. Expand
...
1
2
...