4-Substituted cyclohexyl sulfones as potent, orally active γ-secretase inhibitors

Churcher, Ian; Beher, Dirk; Best, Jonathan D.; Castro, José L.; Clarke, Earl E.; Gentry, Amy L; Harrison, Timothy; Hitzel, Laure; Kay, Euan R.; Kerrad, Sonia; Lewis, Huw D.; Morentin-Gutierrez, Pablo; Mortishire‐Smith, Russell J.; Oakley, Paul; Reilly, Michael; Shaw, Duncan; Shearman, Mark S.; Teall, Martin; Williams, Shirley M.; Wrigley, Jonathan D.J.

doi:10.1016/j.bmcl.2005.10.009

Cited by 75 publications

(59 citation statements)

References 18 publications

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“…We have previously reported a novel series of cyclohexyl sulfone ␥-secretase inhibitors that were able to reduce A␤ levels in SH-SY5Y cells with IC 50 values in the nanomolar range (Churcher et al, 2006). Of these, compound 32 (MRK-560) caused significant reductions of brain A␤(40) levels in the APP-YAC mouse model, with an ED 50 of 1.2 mg/kg 4 h postdosing, which compared very favorably with BMS-299897, which lowered brain A␤ (40), with an ED 50 of 30 mg/kg at 3 h in the APP-YAC mouse (Anderson et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…We have previously reported a potent novel class of bioavailable ␥-secretase inhibitor, MRK-560 (compound 32;Churcher et al, 2006). In SH-SY5Y neuroblastoma cells, this compound inhibited the production of A␤(40) and A␤(42) with similar in vitro IC 50 values in the range of 0.65 nM and reduced A␤(40) in the APP-YAC mouse model with an ED 50 of 1.2 mg/kg.…”

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confidence: 99%

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In Vivo Characterization of Aβ(40) Changes in Brain and Cerebrospinal Fluid Using the Novel γ-Secretase Inhibitor N-[cis-4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) in the Rat

Best¹,

Jay²,

Otu³

et al. 2006

J Pharmacol Exp Ther

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Plaques in the parenchyma of the brain containing A␤ peptides are one of the hallmarks of Alzheimer's disease. These A␤ peptides are produced by the final proteolytic cleavage of the amyloid precursor protein by the intramembraneous aspartyl protease ␥-secretase. Thus, one approach to lowering levels of A␤ has been via the inhibition of the ␥-secretase enzyme. Here, we report a novel, bioavailable ␥-secretase inhibitor, N- [cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) that displayed oral pharmacokinetics suitable for once-a-day dosing. It was able to markedly reduce A␤ in the brain and cerebrospinal fluid (CSF) in the rat, with ED 50 values of 6 and 10 mg/kg, respectively. Time-course experiments using MRK-560 demonstrated these reductions in A␤ could be maintained for 24 h, and comparable temporal reductions in rat brain and CSF A␤ (40) further suggested that these two pools of A␤ are related. This relationship between the brain and CSF A␤ was maintained when MRK-560 was dosed once a day for 2 weeks, and accordingly, when all the data for the dose-response curve and time courses were correlated, a strong association was observed between the brain and CSF A␤ levels. These results demonstrate that MRK-560 is an orally bioavailable ␥-secretase inhibitor with the ability to markedly reduce A␤ peptide in the brain and CSF of the rat and confirm the utility of the rat for assessing the effects of ␥-secretase inhibitors on central nervous system A␤(40) levels in vivo.The neuropathology of AD is characterized by extracellular protein deposits in the brain parenchyma known as plaques, along with intracellular neurofibrillary tangles, which are comprised of hyperphosphorylated tau protein. The plaques are mainly made up of the A␤ proteins A␤(1-40) and (1-42), cleavage products of the APP of which the majority is the more fibrillogenic (1-42) form (Selkoe, 2001). These observations, along with a number of mutations in the APP gene that lead to early onset familial AD, give evidence of the direct involvement of aberrant APP processing in AD (Hardy, 1997).Consequently, much effort has focused on ways to inhibit the production of A␤. The enzymes responsible for processing APP into A␤ are the aspartyl proteases, ␤-site APP cleaving enzyme (␤-secretase) and ␥-secretase (Churcher and Beher, 2005). Although an attractive target for drug discovery, inhibition of ␤-secretase has proved challenging in terms of identification of small molecules for therapeutic use (Selkoe and Schenk, 2003;Middendorp et al., 2004). An alternative strategy has been to inhibit ␥-secretase, an enzyme complex composed of at least four different protein subunits: presenilin (an aspartyl protease, mutations of which are associated with familial AD), nicastrin, APH-1, and PEN-2. ␥-Secretase is responsible for the intramembraneous proteolytic cleavage of the C-terminal fragment of APP, resulting in mainly Article, publication date, and citation information can be found at

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

In Vivo Characterization of Aβ(40) Changes in Brain and Cerebrospinal Fluid Using the Novel γ-Secretase Inhibitor N-[cis-4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) in the Rat

Best¹,

Jay²,

Otu³

et al. 2006

J Pharmacol Exp Ther

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“…Previously, ␥-secretase activity has been investigated in membrane preparations from SHSY5Y cells, HeLa S3 cells and native guinea-pig brain (Li et al, 2000;Grimwood et al, 2005;Churcher et al, 2006). However, the current paper provides the first measure of ␥-secretase activity in rat (a species commonly used to determine the safety aspects of compounds for clinical development) and in the brains of transgenic mice commonly used in AD research.…”

Section: Discussionmentioning

confidence: 94%

A comparative assessment of γ-secretase activity in transgenic and non-transgenic rodent brain

Goggi¹,

Lewis

Mok³

et al. 2006

Journal of Neuroscience Methods

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“…[276] Ein wirksamer und selektiver g-Secretase-Inhibitor mit der Bezeichnung MRK-560 (Abbildung 10) wurde vor kurzem durch eine Gruppe bei Merck publiziert. [277][278][279] Eine dreimonatige Behandlung mit Tg2576 reduzierte das AbPeptid und die Amyloidbelastung im Gehirn, ohne dass Anzeichen einer Hemmung von Notch in Darm, Milz oder Thymus auftraten. Die Selektivität von BMS-299897 und MRK-560 sowie auch das Fehlen von In-vivo-Effekten auf Notch bei LY450139 sind bestechend, die mechanistische Basis dieser Selektivität ist aber noch ungeklärt.…”

Section: Immuntherapie Der Alzheimer-krankheitunclassified

Die Alzheimer‐Demenz: von der Pathologie zu therapeutischen Ansätzen

Jakob‐Roetne

Jacobsen

2009

Angewandte Chemie

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Die gegenwärtigen Strategien zur Entwicklung von Alzheimer‐Therapien sind breit gefächert. Ein verstärktes Augenmerk gilt der Suche nach Hemmstoffen (siehe Bild für zwei Beispiele) der proteolytischen Enzyme β‐ und γ‐Secretase, die die Spaltung des Amyloid‐Vorläuferproteins in Amyloid‐β‐Peptide inhibieren, aus denen die krankheitstypischen Plaque‐Ablagerungen im Gehirn von Alzheimer‐Patienten entstehen.magnified imageDie Forschungen über Altersdemenz und die Alzheimersche Krankheit umfassen ein sehr breites Feld wissenschaftlicher Aktivitäten. So wurden etwa bei der letztjährigen internationalen Tagung der Alzheimer‐Gesellschaft (ICAD 2008 in Chicago) mehr als 2200 Einzelbeiträge präsentiert. Ziel dieses Aufsatzes ist es, einen zusammenhängenden Überblick über das Gebiet zu präsentieren und die wichtigsten Themen und Forschungstrends aufzuzeigen. Die Ausführungen beginnen mit einer Diskussion von Verhaltensabweichungen und sichtbaren pathologischen Befunden, bevor dann auf die molekularen Details der Pathologie eingegangen wird. Besonderes Augenmerk gilt der “Amyloidhypothese” der Alzheimer‐Krankheit, da sie das theoretische Fundament für die meisten der in der Entwicklung befindlichen therapeutischen Konzepte bildet.

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4-Substituted cyclohexyl sulfones as potent, orally active γ-secretase inhibitors

Cited by 75 publications

References 18 publications

In Vivo Characterization of Aβ(40) Changes in Brain and Cerebrospinal Fluid Using the Novel γ-Secretase Inhibitor N-[cis-4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) in the Rat

In Vivo Characterization of Aβ(40) Changes in Brain and Cerebrospinal Fluid Using the Novel γ-Secretase Inhibitor N-[cis-4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) in the Rat

A comparative assessment of γ-secretase activity in transgenic and non-transgenic rodent brain

Die Alzheimer‐Demenz: von der Pathologie zu therapeutischen Ansätzen

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