Discovery of (R)-4-Cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline (ELND006) and (R)-4-Cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridin-3-ylsulfonyl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline (ELND007): Metabolically Stable γ-Secretase Inhibitors that Selectively Inhibit the Production of Amyloid-β over Notch

Probst, Gary D.; Aubele, Danielle L.; Bowers, Simeon; Dressen, Darren; Garofalo, Albert W.; Hom, Roy K.; Konradi, Andrei W.; Marugg, Jennifer L.; Mattson, Matthew N.; Neitzel, Martin L.; Semko, Chris M.; Sham, Hing L.; Smith, Jenifer; Sun, Minghua; Truong, Anh P.; Ye, Xiaocong M.; Xu, Yinchuan; Dappen, Michael S.; Jagodziński, Jacek; Keim, Pamela S.; Peterson, Brian; Latimer, Lee H.; Quincy, David A.; Wu, Jing; Goldbach, Erich; Ness, Daniel; Quinn, Kevin P.; Sauer, John‐Michael; Wong, Karina; Zhang, Hongbin; Zmolek, Wes; Brigham, Elizabeth F.; Kholodenko, Dora; Hu, Kang; Kwong, Grace; Lee, Michael; Liao, Anna; Motter, Ruth; Sacayon, Patricia; Santiago, Pamela; Willits, C. O.; Bard, Frédérique; Bova, Michael P.; Hemphill, Susanna S.; Nguyen, Lam; Ruslim, Lany; Tanaka, Kevin; Tanaka, Pearl; Wallace, William H.; Yednock, Ted; Basi, Guriqbal S.

doi:10.1021/jm301741t

Cited by 29 publications

(26 citation statements)

References 52 publications

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“…Lipid rafts are involved in ␤-and ␥-secretase cleavage of APP (Ehehalt et al, 2003;Vetrivel and Thinakaran, 2010) and in line with our results, it has been shown that alterations in the cholesterol level influence A␤ generation (Refolo et al, 2000;Fassbender et al, 2001;Wahrle et al, 2002;Ghribi et al, 2006). As plant sterols, compared with cholesterol, have a similar sterol backbone, we analyzed whether stigmasterol affects cholesterol distribution and thus ␥-secretase activity in lipid raft membrane microdomains.…”

Section: Stigmasterol Decreases ␥-Secretase Activity By Affecting Chosupporting

confidence: 88%

“…As expected cholesterol significantly increased A␤ levels (122.4% Ϯ 1.3, p Յ 0.001) compared with the solvent control ( Fig. 2A) (Refolo et al, 2000;Fassbender et al, 2001;Refolo et al, 2001;Ghribi et al, 2006;Xiong et al, 2008). Stigmasterol strongly reduced A␤ levels (62.00% Ϯ 3.9, p ϭ 0.0005) ( Fig.…”

Section: Effect Of Plant Sterols and Cholesterol On A␤ Secretionsupporting

confidence: 67%

“…Food products containing plant sterols have been widely used as therapeutic diets or food supplements to lower plasma cholesterol, atherosclerosis risk, and the risk for coronary heart diseases (Plat and Mensink, 2001;Ostlund, 2002;Acuff et al, 2007;CalpeBerdiel et al, 2009). However, up to now it has been controversially discussed whether these lipids are indeed protective.…”

Section: Resultsmentioning

confidence: 99%

“…Stigmasterol-induced effects are all between 10% and 30% and less pronounced compared with e.g., synthetic secretase inhibitors (Shearman et al, 2000;Probst et al, 2013). However, these obviously minor effects on different cellular processes, including direct modulation of enzymes, gene expression, and subcellular transport processes, result in a 38% reduced A␤ generation.…”

Section: Discussionmentioning

confidence: 99%

“…However, previous studies mainly focused on cholesterol, which has been associated with AD pathogenesis (Corder et al, 1993;Kivipelto et al, 2001;Wolozin, 2001;Puglielli et al, 2003). High cholesterol level have been shown to increase A␤ generation whereas suppression of cholesterol de novo synthesis strongly reduces A␤ release in vivo and in vitro (Fassbender et al, 2001;Refolo et al, 2001;Shie et al, 2002;Ghribi et al, 2006). Cholesterol is an essential component of cellular membranes and is highly enriched in detergentresistant membrane microdomains, called lipid rafts (Simons and Ikonen, 1997), which have been implicated in amyloidogenic APP processing (Ehehalt et al, 2003;Vetrivel and Thinakaran, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Plant Sterols the Better Cholesterol in Alzheimer's Disease? A Mechanistical Study

Burg¹,

Grimm²,

Rothhaar³

et al. 2013

J. Neurosci.

110

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Amyloid-␤ (A␤), major constituent of senile plaques in Alzheimer's disease (AD), is generated by proteolytic processing of the amyloid precursor protein (APP) by ␤-and ␥-secretase. Several lipids, especially cholesterol, are associated with AD. Phytosterols are naturally occurring cholesterol plant equivalents, recently been shown to cross the blood-brain-barrier accumulating in brain. Here, we investigated the effect of the most nutritional prevalent phytosterols and cholesterol on APP processing. In general, phytosterols are less amyloidogenic than cholesterol. However, only one phytosterol, stigmasterol, reduced A␤ generation by (1) directly decreasing ␤-secretase activity, (2) reducing expression of all ␥-secretase components, (3) reducing cholesterol and presenilin distribution in lipid rafts implicated in amyloidogenic APP cleavage, and by (4) decreasing BACE1 internalization to endosomal compartments, involved in APP ␤-secretase cleavage. Mice fed with stigmasterol-enriched diets confirmed protective effects in vivo, suggesting that dietary intake of phytosterol blends mainly containing stigmasterol might be beneficial in preventing AD.

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Section: Stigmasterol Decreases ␥-Secretase Activity By Affecting Chosupporting

confidence: 88%

Section: Effect Of Plant Sterols and Cholesterol On A␤ Secretionsupporting

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Plant Sterols the Better Cholesterol in Alzheimer's Disease? A Mechanistical Study

Burg¹,

Grimm²,

Rothhaar³

et al. 2013

J. Neurosci.

110

View full text Add to dashboard Cite

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Synthesis of Pyrazolo[4,3‐c]quinolines from Morita–Baylis–Hillman Adducts of 2‐Bromobenzaldehydes

Moon

Lim

et al. 2015

Bulletin Korean Chem Soc

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The synthesis of pyrazolo [4,3-c]quinolines has been carried out from the Morita-Baylis-Hillman bromides of 2-bromobenzaldehydes and methyl vinyl ketone. The synthesis involved a novel one-pot preparation of functionalized pyrazoles from α,β-enones, a one-pot Cu-mediated intramolecular N-arylation, and the elimination of p-toluenesulfinic acid.Compound 2e: 63%; white solid, m.p. 166-168 C; IR (KBr) 3274, 1502, 1327, 1161 cm −1 ; 1 H NMR (CDCl 3 , 300 MHz) δ 1.28 (t, J = 7.5 Hz, 3H), 2.41 (s, 3H), 2.66 (q, J = 7.5 Hz, 2H), 3.74 (dd, J = 12.9 and 4.5 Hz, 1H), 3.91 (dd, J = 12.9 and 6.6 Hz, 1H), 4.28 (dd, J = 6.6 and 4.5 Hz, 1H), 7.04-7.09 (m, 1H), 7.12-7.27 (m, 9H), 7.47-7.52 (m, 1H), 7.62 (d, J = 8.4 Hz, 2H); 13 C NMR (CDCl 3 , 75 MHz) δ

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Pharmacokinetic and Pharmacodynamic Effects of a γ‐Secretase Modulator, PF‐06648671, on CSF Amyloid‐β Peptides in Randomized Phase I Studies

Ahn

Carrieri

Cruz

et al. 2019

Clin Pharma and Therapeutics

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γ-Secretase modulators (GSMs) represent a promising therapy for Alzheimer's disease by reducing pathogenic amyloid-β (Aβ) peptide production. Three phase I studies (NCT02316756, NCT02407353, and NCT02440100) investigated the safety/tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the oral GSM, PF-06648671. A PK/PD indirect-response model was developed (using biomarker data) to simultaneously characterize differential effects of PF-06648671 on multiple Aβ species in cerebrospinal fluid (CSF). Healthy subjects (n = 120) received single doses or multiple-ascending doses of PF-06648671/placebo for 14 days. No serious adverse events occurred; severe adverse events were deemed not drug related. PF-06648671 decreased Aβ42 and Aβ40 concentrations in CSF, with greater effects on Aβ42, and increased Aβ37 and Aβ38 levels, particularly Aβ37. No significant change in total Aβ was observed. The PK/PD model well described the tendency of observed CSF Aβ data and the steady-state effects of PF-06648671, supporting its use for predicting central Aβ effects and optimal dose selection for GSMs in future trials.Dementia is a progressive, neurodegenerative disorder affecting ~ 50 million people worldwide, 1 of which Alzheimer's disease (AD) is most common. 1 Treatments including cholinesterase inhibitors and N-methyl-d-aspartate receptor antagonists help with AD symptoms. 2 However, a medical need exists for agents capable of modifying and slowing AD progression. AD pathology in the brain is characterized by senile, amyloid plaques comprising a core of amyloid-β (Aβ) peptide fibrils, 3,4 and neurofibrillary tangles of primarily hyperphosphorylated tau protein. 4,5 Amyloid precursor protein (APP) is a transmembrane protein that is cleaved during processing by γ-secretase to generate Aβ peptides of various lengths, including Aβ37,38,40, and 42. 6,7 Aβ42 has a higher aggregation

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Cited by 29 publications

References 52 publications

Plant Sterols the Better Cholesterol in Alzheimer's Disease? A Mechanistical Study

Plant Sterols the Better Cholesterol in Alzheimer's Disease? A Mechanistical Study

Synthesis of Pyrazolo[4,3‐c]quinolines from Morita–Baylis–Hillman Adducts of 2‐Bromobenzaldehydes

Pharmacokinetic and Pharmacodynamic Effects of a γ‐Secretase Modulator, PF‐06648671, on CSF Amyloid‐β Peptides in Randomized Phase I Studies

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