Design and Synthesis of a Novel Series of Bicyclic Heterocycles As Potent γ-Secretase Modulators

Bischoff, François; Berthelot, Didier; Cleyn, Michel De; Macdonald, Gregor; Minne, Garrett; Oehlrich, Daniel; Pieters, Serge; Surkyn, Michel; Trabanco, Andrés A.; Tresadern, Gary; Brandt, Sven Van; Velter, Ingrid; Zaja, Mirko; Borghys, Herman; Masungi, Chantal; Mercken, Marc; Gijsen, Harrie J. M.

doi:10.1021/jm201710f

Cited by 60 publications

(42 citation statements)

References 53 publications

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“…Carboxylic acid JNJ-40418677 ( 4 ) has lowered A β 42 in cells with an IC 50 of 200 nM and had a brain/plasma ratio of 0.5–1.0 in mice, depending on the dose [16]. Imidazole JNJ-42601572 ( 5 ) lowered A β 42 in cells with an IC 50 of 16 nM and had a brain/plasma ratio of 0.7–1.1 in mice [15, 17]. A time profile of JNJ-42601572 in mouse is shown in Figure 3.…”

Section: Discussionmentioning

confidence: 99%

“…For the cellular in vitro activity of our own compounds, screening was carried out using SKNBE2 human neuroblastoma cells carrying the hAPP 695 wild-type as described in [15]. For a description of the mouse in vivo experiments, see references [15, 16]; for details on the dog in vivo experiments, see [17].…”

Section: Methodsmentioning

confidence: 99%

“…For a description of the mouse in vivo experiments, see references [15, 16]; for details on the dog in vivo experiments, see [17]. …”

Section: Methodsmentioning

confidence: 99%

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-Secretase Modulators: Can We Combine Potency with Safety?

Gijsen

Mercken

2012

International Journal of Alzheimer's Disease

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γ-Secretase modulation has been proposed as a potential disease modifying anti-Alzheimer's approach. γ-Secretase modulators (GSMs) cause a product shift from the longer amyloid-beta (Aβ) peptide isoforms to shorter, more soluble, and less amyloidogenic isoforms, without inhibiting APP or Notch proteolytic processing. As such, modulating γ-secretase may avoid some of the adverse effects observed with γ-secretase inhibitors. Since the termination of the GSM tarenfurbil in 2008 due to negative phase III trial results, a considerable progress has been made towards more potent and better brain penetrable compounds. However, an analysis of their lipophilic efficiency indices indicates that their increased potency can be largely attributed to their increased lipophilicity. The need for early and chronic dosing with GSMs will require high-safety margins. This will be a challenge to achieve with the current, highly lipophilic GSMs. We will demonstrate that by focusing on the drug-like properties of GSMs, a combination of high in vitro potency and reduced lipophilicity can be achieved and does result in better tolerated compounds. The next hurdle will be to translate this knowledge into GSMs which are highly efficacious and safe in vivo.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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-Secretase Modulators: Can We Combine Potency with Safety?

Gijsen

Mercken

2012

International Journal of Alzheimer's Disease

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“…Furthermore, γ-secretase modulators have emerged as a potential disease-modifying treatment for AD. The imidazole-containing benzimidazole 14 was identified as a γ-secretase modulators with low nanomolar activity in vitro and concomitant promising potency in vivo (mouse, rat and dog model) through a conformational lock of pyridine in lead compound 13 into bicyclic pyridone isostere (Figure 1) [22].…”

Section: Key Termsmentioning

confidence: 99%

Conformational Restriction: An Effective Tactic in ‘Follow-On’-Based Drug Discovery

et al. 2014

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The conformational restriction (rigidification) of a flexible ligand has often been a commonly used strategy in drug design, as it can minimize the entropic loss associated with the ligand adopting a preferred conformation for binding, which leads to enhanced potency for a given physiological target, improved selectivity for isoforms and reduced the possibility of drug metabolism. Therefore, the application of conformational restriction strategy is a core aspect of drug discovery and development that is widely practiced by medicinal chemists either deliberately or subliminally. The present review will highlight current representative examples and a brief overview on the rational design of conformationally restricted agents as well as discuss its advantages over the flexible counterparts.

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“…The result of the secondary cleavage is an APP intracellular domain and fragments of Ab with varying lengths of amino acids including peptides of 40 (Ab 40 ) and 42 (Ab 42 ) amino acids. It is believed that Ab-proteins, as proteolytic degradants of amyloid precursor protein (APP), are critical to the degeneration and loss of neurons and the onset of symptoms of dementia.…”

Section: Alzheimer's Diseasementioning

confidence: 99%