N-(5-Chloro-2-(hydroxymethyl)-N-alkyl-arylsulfonamides as γ-secretase inhibitors

Parker, Michael F.; Barten, Donna M.; Bergstrom, Carl P.; Bronson, Joanne J.; Corsa, Jason A.; Deshpande, Milind; Felsenstein, Kevin M.; Guss, Valerie; Hansel, Steven; Johnson, Graham; Keavy, Daniel J.; Lau, Wai Y.; Möck, J.; Prasad, C. V. C.; Polson, Craig; Sloan, Charles P.; Smith, David W.; Wallace, Owen B.; Wang, Henry H.; Williams, A. Stanley; Zheng, Ming

doi:10.1016/j.bmcl.2007.06.022

Cited by 10 publications

(4 citation statements)

References 7 publications

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“…Indeed, a first generation aryl sulfonamide GSI, BMS299897 [10,11,88], was demonstrated to avoid Notch inhibition endpoints in the gastro-intestinal tract in a preclinical safety model [28]. Additional arylsulfonamide analogs related to BMS299897 [89], as well as aminocaprolactam sulfonamides related to ELN318463 have been described [79,90]. The APP selectivity of the sulfonamide core appears to be very sensitive to structural modifications.…”

Section: Discussionmentioning

confidence: 99%

Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease

Basi

Hemphill

Brigham

et al. 2010

Alzheimers Res Ther

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IntroductionInhibition of gamma-secretase presents a direct target for lowering Aβ production in the brain as a therapy for Alzheimer's disease (AD). However, gamma-secretase is known to process multiple substrates in addition to amyloid precursor protein (APP), most notably Notch, which has limited clinical development of inhibitors targeting this enzyme. It has been postulated that APP substrate selective inhibitors of gamma-secretase would be preferable to non-selective inhibitors from a safety perspective for AD therapy.MethodsIn vitro assays monitoring inhibitor potencies at APP γ-site cleavage (equivalent to Aβ40), and Notch ε-site cleavage, in conjunction with a single cell assay to simultaneously monitor selectivity for inhibition of Aβ production vs. Notch signaling were developed to discover APP selective gamma-secretase inhibitors. In vivo efficacy for acute reduction of brain Aβ was determined in the PDAPP transgene model of AD, as well as in wild-type FVB strain mice. In vivo selectivity was determined following seven days x twice per day (b.i.d.) treatment with 15 mg/kg/dose to 1,000 mg/kg/dose ELN475516, and monitoring brain Aβ reduction vs. Notch signaling endpoints in periphery.ResultsThe APP selective gamma-secretase inhibitors ELN318463 and ELN475516 reported here behave as classic gamma-secretase inhibitors, demonstrate 75- to 120-fold selectivity for inhibiting Aβ production compared with Notch signaling in cells, and displace an active site directed inhibitor at very high concentrations only in the presence of substrate. ELN318463 demonstrated discordant efficacy for reduction of brain Aβ in the PDAPP compared with wild-type FVB, not observed with ELN475516. Improved in vivo safety of ELN475516 was demonstrated in the 7d repeat dose study in wild-type mice, where a 33% reduction of brain Aβ was observed in mice terminated three hours post last dose at the lowest dose of inhibitor tested. No overt in-life or post-mortem indications of systemic toxicity, nor RNA and histological end-points indicative of toxicity attributable to inhibition of Notch signaling were observed at any dose tested.ConclusionsThe discordant in vivo activity of ELN318463 suggests that the potency of gamma-secretase inhibitors in AD transgenic mice should be corroborated in wild-type mice. The discovery of ELN475516 demonstrates that it is possible to develop APP selective gamma-secretase inhibitors with potential for treatment for AD.

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Section: Discussionmentioning

confidence: 99%

Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease

Basi

Hemphill

Brigham

et al. 2010

Alzheimers Res Ther

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“…Recent Advances in Alternative Binding-Site-Based GSIs: Arylsulfonamide-Containing GSIs and Related Compounds Independent of Amgen's early work on arylsulfonamides, 91 the Bristol-Myers Squibb group had identified lead arylsulfonamides from an HTS screening campaign. 92 Employing a cellular assay (hAPP swe H4 cells), they identified 31 (Figure 15) as the initial arylsulfonamide lead (Aβ 40 IC 50 =850 nM in hAPP swe H4 cells). Significant enhancement in GSI potency (∼10-fold) resulted from branching with an R-methyl group at the point of attachment to the sulfonamide nitrogen with the R isomer being the eutomer.…”

Section: Recent Advances In Alternative Binding-site-based Gsis: Carb...mentioning

confidence: 99%

“…Independent of Amgen’s early work on arylsulfonamides, the Bristol-Myers Squibb group had identified lead arylsulfonamides from an HTS screening campaign . Employing a cellular assay (hAPP swe H4 cells), they identified 31 (Figure ) as the initial arylsulfonamide lead (Aβ 40 IC 50 = 850 nM in hAPP swe H4 cells).…”

Section: Recent Advances In Alternative Binding-site-based Gsis: Aryl...mentioning

confidence: 99%

Recent Advances in the Identification of γ-Secretase Inhibitors To Clinically Test the Aβ Oligomer Hypothesis of Alzheimer’s Disease

2009

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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.…”

Section: C-secretase Inhibitorsmentioning

confidence: 95%

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

Wu¹,

Zhang²

2009

Drug Development Research

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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 bpeptide (Ab). The accumulation and deposition of Ab eventually lead to neuronal damage and cell death. Ab peptides are generated from a large precursor protein (APP) by b-secretase (BACE) and g-secretase.Reduction of Ab by inhibition of g-secretase may prevent Ab-mediated downstream neurotoxic events, representing an attractive strategy to combat Alzheimer's disease. g-Secretase is a multi-component complex comprised of four distinct units: presenilin, nicastrin, aph-1, and pen2. In addition to processing APP, g-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 g-secretase inhibitors. It is imperative to balance the therapeutic efficacy and the risk of mechanism-based toxicity. Drug Dev Res 70 : 94-100, 2009.

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N-(5-Chloro-2-(hydroxymethyl)-N-alkyl-arylsulfonamides as γ-secretase inhibitors

Cited by 10 publications

References 7 publications

Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease

Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease

Recent Advances in the Identification of γ-Secretase Inhibitors To Clinically Test the Aβ Oligomer Hypothesis of Alzheimer’s Disease

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

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