Previously, chemistry effort on the gem-cyclohexane series of gamma-secretase inhibitors has focused on the 4-position of the cyclohexane ring. Recently chemistry has been directed towards the 3-position and substitution here has also provided compounds with high gamma-secretase activity.
"modelling playing a role in defining the conformational and pharmacophoric properties of these compounds [Asberom et al., 2007a; Guo et al., 2007; Harrison et al., 2006; Jelley et al., 2006; Pissarnitski et al., 2006, 2007; Pu et al., 2007; Scott et al., 2007; Shaw et al., 2006]. "
"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. "
[Show abstract][Hide abstract] ABSTRACT: Inhibition of BACE and γ-secretase, and modulation of γ-secretase, represent promising strategies to reduce Aβ peptides in brain. Reports of BACE inhibitors with in vivo activity in animal models have appeared from several laboratories, demonstrating that the challenge of brain penetration for this class of inhibitors is not insurmountable. Considerable progress has been made in understanding Notch-related toxicities of γ-secretase inhibitors, and Aβ reductions in the absence of these side effects have been reported. The field of γ-secretase modulators is relatively immature, but late stage clinical studies are in progress with an NSAID-derived modulator. There is anticipation that data addressing the validity of the amyloid hypothesis will be reported in the near future as BACE and γ-secretase targeted therapies move into clinical development.
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