3-Substituted gem-cyclohexane sulfone based γ-secretase inhibitors for Alzheimer's disease: Conformational analysis and biological activity

Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK.
Bioorganic & Medicinal Chemistry Letters (Impact Factor: 2.42). 08/2006; 16(14):3839-42. DOI: 10.1016/j.bmcl.2006.04.019
Source: PubMed


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.

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    • "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]. "
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    ABSTRACT: This review discusses the involvement of structure and modeling in the design of β-secretase (BACE-1) and -secretase inhibitors as putative Alzheimer's Disease therapeutics. The early and broad availability of structural information for BACE-1, a membrane-tethered aspartyl protease, has led to the use of in silico methods in the overall design and optimization process. However, for -secretase, an integral membrane protein, the lack of a detailed 3D structure has limited the application of computational methods. Drug Dev Res 70, 2009. © 2009 Wiley-Liss, Inc.
    Drug Development Research 03/2009; 70(2):70 - 93. DOI:10.1002/ddr.20291 · 0.77 Impact Factor
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    • "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. "
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    ABSTRACT: Alzheimer's disease is a neurodegenerative disorder manifested by cognitive and memory deterioration, impairment of language, and other activities of daily life. Two major pathological hallmarks are characteristics of Alzheimer's disease: intracellular neurofibrillary tangles and extracellular amyloid plaques. The amyloid plaque is mainly comprised of aggregated form of the 40–42 residue amyloid β-peptide (Aβ). The accumulation and deposition of Aβ eventually lead to neuronal damage and cell death. Aβ peptides are generated from a large precursor protein (APP) by β-secretase (BACE) and γ-secretase. Reduction of Aβ by inhibition of γ-secretase may prevent Aβ-mediated downstream neurotoxic events, representing an attractive strategy to combat Alzheimer's disease. γ-Secretase is a multi-component complex comprised of four distinct units: presenilin, nicastrin, aph-1, and pen2. In addition to processing APP, γ-secretase has also been implicated in the cleavage of other substrates, the most notable one being the Notch receptor. Inhibition of Notch processing is the key factor of mechanism-based side effects associated with γ-secretase inhibitors. It is imperative to balance the therapeutic efficacy and the risk of mechanism-based toxicity. Drug Dev Res 70, 2009. © 2009 Wiley-Liss, Inc.
    Drug Development Research 03/2009; 70(2):94 - 100. DOI:10.1002/ddr.20288 · 0.77 Impact Factor
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    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.
    Annual reports in medicinal chemistry 01/2007; 42:27-47. DOI:10.1016/S0065-7743(07)42003-6 · 1.36 Impact Factor
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