Hydroxytriamides as potent γ-secretase inhibitors

Prasad, C. V. C.; Noonan, Jeffrey W.; Sloan, Charles P.; Lau, Wai Y.; Vig, Shikha; Parker, Michael F.; Smith, David W.; Hansel, Steven; Polson, Craig; Barten, Donna M.; Felsenstein, Kevin M.; Roberts, Susan B.

doi:10.1016/j.bmcl.2004.01.086

Cited by 26 publications

(6 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…7) accounting for use of transition-state analogs or photoaffinity-coupled peptides comparable to those that target viral HIV proteases [338,365] and synthesis of derivatives to improve penetration and efficacy that include difluoroketones, aldehydes, expoxides and hydroxy-ethyl, or triamides active at pM-lM levels in vitro [333,344,[366][367][368][369].…”

Section: C-sc Inhibitionmentioning

confidence: 99%

BACE and γ-Secretase Characterization and Their Sorting as Therapeutic Targets to Reduce Amyloidogenesis

Marks

Berg

2009

Neurochem Res

View full text Add to dashboard Cite

Secretases are named for enzymes processing amyloid precursor protein (APP), a prototypic type-1 membrane protein. This led directly to discovery of novel Aspartyl proteases (beta-secretases or BACE), a tetramer complex gamma-secretase (gamma-SC) containing presenilins, nicastrin, aph-1 and pen-2, and a new role for metalloprotease(s) of the ADAM family as a alpha-secretases. Recent advances in defining pathways that mediate endosomal-lysosomal-autophagic-exosomal trafficking now provide targets for new drugs to attenuate abnormal production of fibril forming products characteristic of AD. A key to success includes not only characterization of relevant secretases but mechanisms for sorting and transport of key metabolites to abnormal vesicles or sites for assembly of fibrils. New developments we highlight include an important role for an 'early recycling endosome' coated in retromer complex containing lipoprotein receptor LRP-II (SorLA) for switching APP to a non-amyloidogenic pathway for alpha-secretases processing, or to shuttle APP to a 'late endosome compartment' to form Abeta or AICD. LRP11 (SorLA) is of particular importance since it decreases in sporadic AD whose etiology otherwise is unknown.

show abstract

Section: C-sc Inhibitionmentioning

confidence: 99%

BACE and γ-Secretase Characterization and Their Sorting as Therapeutic Targets to Reduce Amyloidogenesis

Marks

Berg

2009

Neurochem Res

View full text Add to dashboard Cite

show abstract

“…Finally, we successfully utilized α-hydroxythioesters for the coupling reagent-free synthesis of optically pure α-hydroxyamides, which are very important drug candidates in the pharmaceutical industry333435363738 (Fig. 4a).…”

Section: Resultsmentioning

confidence: 99%

Biomimetic catalytic transformation of toxic α-oxoaldehydes to high-value chiral α-hydroxythioesters using artificial glyoxalase I

et al. 2017

View full text Add to dashboard Cite

Glyoxalase I plays a critical role in the enzymatic defence against glycation by catalysing the isomerization of hemithioacetal, formed spontaneously from cytotoxic α-oxoaldehydes and glutathione, to (S)-α-hydroxyacylglutathione derivatives. Upon the hydrolysis of the thioesters catalysed by glyoxalase II, inert (S)-α-hydroxy acids, that is, lactic acid, are then produced. Herein, we demonstrate highly enantioselective glyoxalase I mimic catalytic isomerization of in-situ-generated hemithioacetals, providing facile access to both enantiomers of α-hydroxy thioesters. Owing to the flexibility of thioesters, a family of optically pure α-hydroxyamides, which are highly important drug candidates in the pharmaceutical industry, were prepared without any coupling reagents. Similar to real enzymes, the enforced proximity of the catalyst and substrates by the chiral cage in situ formed by the incorporation of potassium salt can enhance the reactivity and efficiently transfer the stereochemical information.

show abstract

“…In an interesting transition from isostere structures to inhibitors having similarity to DAPT, Bristol-Myers Squibb scientists followed up a hydroxyethylene isostere screening hit (20) (IC 50 = 4.7 μM in cells) by modifying the N-terminal naphthylene group and replacing the isostere with simpler amides [52], a process which led to the considerably more potent amide (21) (IC 50 = 1 nM) (Fig. 8).…”

Section: Azepine -Secretase Inhibitorsmentioning

confidence: 98%

Recent Progress in the Medicinal Chemistry of γ-Secretase Inhibitors

Olson¹,

Albright²

2008

CTMC

View full text Add to dashboard Cite

Abeta is implicated in the initiation and progression of Alzheimer's disease (AD) by the phenotypic analysis of mutations in three human genes that lead to inherited, early forms of AD and data from preclinical studies. Based on this evidence, gamma-secretase inhibitors are being actively pursued as potential AD therapeutics to reduce Abeta formation. This manuscript reviews recent progress in the medicinal chemistry of three major classes of gamma-secretase inhibitors: peptide isosteres, azepines, and sulfonamides. Peptide isosteres have been useful for demonstrating that presenilin is the catalytic subunit of gamma-secretase and probing the active site. The peptidic nature of these inhibitors has, however, interfered with their utility for in vivo studies. Instead, the pharmaceutical industry has focused on optimizing azepines and sulfonamides. Both azepines and sulfonamides bind to a common, allosteric site on presenilin that differs from the active site identified by the peptide isosteres. Significant progress in the optimization of both azepines and sulfonamides has led to compounds that inhibit brain Abeta synthesis in preclinical models and has culminated in the identification of gamma-secretase inhibitors, including LY-450139 and MK-0752, for human trials.

show abstract

Hydroxytriamides as potent γ-secretase inhibitors

Cited by 26 publications

References 29 publications

BACE and γ-Secretase Characterization and Their Sorting as Therapeutic Targets to Reduce Amyloidogenesis

BACE and γ-Secretase Characterization and Their Sorting as Therapeutic Targets to Reduce Amyloidogenesis

Biomimetic catalytic transformation of toxic α-oxoaldehydes to high-value chiral α-hydroxythioesters using artificial glyoxalase I

Recent Progress in the Medicinal Chemistry of γ-Secretase Inhibitors

Contact Info

Product

Resources

About

Hydroxytriamides as potent γ-secretase inhibitors

Cited by 26 publications

References 29 publications

BACE and γ-Secretase Characterization and Their Sorting as Therapeutic Targets to Reduce Amyloidogenesis

BACE and γ-Secretase Characterization and Their Sorting as Therapeutic Targets to Reduce Amyloidogenesis

Biomimetic catalytic transformation of toxic α-oxoaldehydes to high-value chiral α-hydroxythioesters using artificial glyoxalase I

Recent Progress in the Medicinal Chemistry of &#947;-Secretase Inhibitors

Contact Info

Product

Resources

About

Recent Progress in the Medicinal Chemistry of γ-Secretase Inhibitors