Fluorinated piperidine acetic acids as γ-secretase modulators

Stanton, Matthew; Hubbs, Jed L.; Sloman, David L.; Hamblett, Christopher L.; Andrade, Paula B.; Angagaw, Minilik; Bi, Grace; Black, Regina M.; Crispino, Jamie L.; Cruz, Jonathan C.; Fan, Eric; Farris, Georgia M.; Hughes, Bethany; Kenific, Candia M.; Middleton, Richard E.; Nikov, George N.; Sajonz, Peter; Shah, Sanjiv; Shomer, Nirah H.; Szewczak, Alexander A.; Tanga, Flobert; Tudge, Matthew T.; Shearman, Mark S.; Muñoz, Benito

doi:10.1016/j.bmcl.2009.11.034

Cited by 30 publications

(14 citation statements)

References 27 publications

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“…16 ) with adequate bioavailability and in vivo clearance. A satisfactory 53% brain/plasma drug concentration ratio has been described for compound 21 in rats, resulting in a dose-dependant lowering of Aβ42 brain levels with an 1 µM IC 50 [105, 190]. The presented structures further suggest interplay between the lipophilicity and steric bulk of the substituents.…”

Section: Chemical Development and Clinical Perspective Of γ-Secretasementioning

confidence: 92%

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Chemical Biology, Molecular Mechanism and Clinical Perspective of γ - Secretase Modulators in Alzheimers Disease

Bulic¹,

Neß²,

Hahn³

et al. 2011

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Comprehensive evidence supports that oligomerization and accumulation of amyloidogenic Aβ42 peptides in brain is crucial in the pathogenesis of both familial and sporadic forms of Alzheimer's disease. Imaging studies indicate that the buildup of Aβ begins many years before the onset of clinical symptoms, and that subsequent neurodegeneration and cognitive decline may proceed independently of Aβ. This implies the necessity for early intervention in cognitively normal individuals with therapeutic strategies that prioritize safety. The aspartyl protease γ-secretase catalyses the last step in the cellular generation of Aβ42 peptides, and is a principal target for anti-amyloidogenic intervention strategies. Due to the essential role of γ-secretase in the NOTCH signaling pathway, overt mechanism-based toxicity has been observed with the first generation of γ-secretase inhibitors, and safety of this approach has been questioned. However, two new classes of small molecules, γ-secretase modulators (GSMs) and NOTCH-sparing γ-secretase inhibitors, have revitalized γ-secretase as a drug target in AD. GSMs are small molecules that cause a product shift from Aβ42 towards shorter and less toxic Ab peptides. Importantly, GSMs spare other physiologically important substrates of the γ-secretase complex like NOTCH. Recently, GSMs with nanomolar potency and favorable in vivo properties have been described. In this review, we summarize the knowledge about the unusual proteolytic activity of γ-secretase, and the chemical biology, molecular mechanisms and clinical perspective of compounds that target the γ-secretase complex, with a particular focus on GSMs.

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Section: Chemical Development and Clinical Perspective Of γ-Secretasementioning

confidence: 92%

“…A close analogue of GSM-1 ( 21 , Fig. 16 ) displayed an IC 50 for Aβ42 inhibition of 640 nM (A(40 IC 50 > 10 µM) without observable inhibition of Notch processing at the maximum assay concentration (10 µM) [105]. In addition, a potent non-acidic GSM ( 9 , Fig.…”

Section: Molecular Mechanism Of γ-Secretase Inhibitors and Modulatorsmentioning

confidence: 99%

Chemical Biology, Molecular Mechanism and Clinical Perspective of γ - Secretase Modulators in Alzheimers Disease

Bulic¹,

Neß²,

Hahn³

et al. 2011

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“…No specific Ab42 IC 50 values were provided, but the compounds were reported to be 2-to 50-fold selective for lowering Ab42 over Ab40. Similar piperdin-4-yl acetic acids were reported to have submicromolar potency in vitro, favorable rodent PK and in vivo efficacy in APP-YAC transgenic mice [49,50].…”

Section: Nsaid/carboxylic Acid Type Gsmsmentioning

confidence: 97%

Novel γ-secretase modulators: a review of patents from 2008 to 2010

Pettersson

Kauffman

Ende

et al. 2011

Expert Opinion on Therapeutic Patents

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Much progress has been made in the past 2 years on developing GSMs with improved potency for lowering the production of Aβ42. However, many of these chemotypes are in a challenging chemical space and generally possess higher lipophilicity than most CNS drugs. It will be important to gain a better understanding of the specific target(s) that these GSMs interact with in order to facilitate future drug design efforts.

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“…Though for AD treatment, the γ-secretase inhibition is an smart strategy, it has led to undesirable adverse events in clinical trials, such as notably gastrointestinal toxicity [62,63]. These side effects are associated with blocking the processing of Notch, which are a transmembrane receptor signaling protein and also a γ-secretase substrate [64]. The modulation of γ-secretase is a possible strategy to avoid Notchrelated toxicity.…”

Section: Figure 1 -Amyloid Cascade Hypothesismentioning

confidence: 99%

“…The modulation of γ-secretase is a possible strategy to avoid Notchrelated toxicity. To selectively inhibit the production of Aβ42 while not affecting the production of Aβ40 or Notch processing, certain nonsteroidal anti-inflammatory drugs (NSAIDs) were created [64][65][66][67][68][69] (figure 3). Regarding to β-secretase, BACE1 is a prime drug target for inhibiting the production of Aβ.…”

Section: Figure 1 -Amyloid Cascade Hypothesismentioning

confidence: 99%

The Potential Effect of Fluorinated Compounds in the Treatment of Alzheimer’s Disease

Gomes¹,

Loureiro²,

Coelho³

et al. 2015

CPD

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Drug development for neurodegenerative diseases such as Alzheimer disease (AD) is a challenge not only due to the cellular molecular mechanisms involved but also because the inherent difficulty of most molecules to cross the blood-brain-barrier (BBB). To overcome these drawbacks, a promising approach is the development of fluorinated molecules and supramolecular assemblies.This review focus on the therapeutic potential of new fluorinated molecules developed as active and selective agents for AD to achieve the desired properties in terms of pharmacokinetic/pharmacodynamics and BBB targeting. The methods to fluorinate organic molecules are described and a brief characterization of the mechanisms of AD progression and therapeutic approaches are also addressed.The paradigm of cell biology knowledge and fluorine biochemistry is highlighted, such as organofluorine inhibitors of amyloid fibrilogenesis.

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Fluorinated piperidine acetic acids as γ-secretase modulators

Cited by 30 publications

References 27 publications

Chemical Biology, Molecular Mechanism and Clinical Perspective of γ - Secretase Modulators in Alzheimers Disease

Chemical Biology, Molecular Mechanism and Clinical Perspective of γ - Secretase Modulators in Alzheimers Disease

Novel γ-secretase modulators: a review of patents from 2008 to 2010

The Potential Effect of Fluorinated Compounds in the Treatment of Alzheimer’s Disease

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