Modulators and Inhibitors of γ- and β-Secretases

Abstract

Most gene mutations associated with Alzheimer’s disease point to the metabolism of amyloid precursor protein as a potential cause. The β- and γ-secretases are two executioners of amyloid precursor protein processing resulting in amyloid-β. Significant progress has been made in the selective inhibition of both proteases, regardless of structural information for γ-secretase. Several peptidic and nonpeptidic leads were identified for both targets.

Curcumin Derivatives Inhibit or Modulate Beta-Amyloid Precursor Protein Metabolism

“…1 ) and particularly suppressed the formation of A ␤ 40 . This supports the contribution of the carboxylic acid to the structure activity relationship of arylacetic acids as ␥ -secretase modulators [40,41] . Curcumin 1 and the compounds 4a-c and 4f-i displayed cellular toxicity at 40 M , whereas 4e displayed cellular toxicity at 20 M concentration.…”

“…The oxazole derivatives of curcumin were prepared as depicted in scheme 1. The diketone functionality of curcumin was cyclized to its corresponding oxazole by refluxing it with hydroxylamine hydrochloride and pyridine in ethanol for 18 h. The recent identification of potent ␥ -secretase modulators deriving from carprofen and carbazoles featuring carboxylic substituents stimulated us to add this moiety to the curcumin scaffold [40,41] . The phenolic curcumin-oxazoles were O-alkylated using 2-chloro t -butyl acetate and anhydrous K 2 CO 3 at 60-70 ° C for 12 h to give the bisalkylated compound 2.…”

N-Substituted carbazolyloxyacetic acids modulate Alzheimer associated γ-secretase

“…[17][18][19][20] Recently, we reported N-sulfonylated and Nalkylated derivatives (2, 3) of carprofen (Scheme 1) that modulate c-secretase and selectively reduce Ab 42 . 21,22 This is accompanied by an increase of the less aggregatory Ab 38 species. Carprofen 1 is a COX-2 inhibitor (COX = cyclooxygenase) approved for the use in dogs, cows and horses as Imadyl Ò or Rimadyl Ò .…”

γ‐secretase inhibitors for the treatment of Alzheimer's disease

“…Although these analogues are valuable tools in purifying g-secretase and elucidating its mechanism and function [Fraering et al, 2004;Li et al, 2000;Esler et al, 2000], they were deemed less feasible for in vivo studies and further development as orally available drugs. During the past few years, a number of low-molecular-weight, more drug-like small molecules with high potency have been disclosed in the scientific and patent literature [Laras et al, 2005;Lewis et al, 2005;Keerti et al, 2005;Gundersen et al, 2005;Teall et al, 2005;Sparey et al, 2005;Churcher et al, 2006;Thompson et al, 2006;Shaw et al, 2006;Jelley et al, 2006;Scott et al, 2006;Pissarnitski et al, 2007;Narlawar et al, 2007;Asberom et al, 2007;Scott et al, 2007;Parker et al, 2007; for patents, see reviews by Larner, 2004;Harrison et al, 2004;Nguyen et al, 2006;Ziani-Cherif et al, 2006;Beher and Graham, 2005;Churcher and Beher, 2005;Schmidt et al, 2006]. This is the focus of the current overview.…”