Studies of Aβ Pharmacodynamics in the Brain, Cerebrospinal Fluid, and Plasma in Young (Plaque-Free) Tg2576 Mice Using the γ-Secretase Inhibitor N2-[(2S)-2-(3,5-Difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY-411575)

Lanz, Thomas A.; Hosley, John D.; Adams, Wade J.; Merchant, Kalpana

doi:10.1124/jpet.103.060715

Cited by 131 publications

(117 citation statements)

References 22 publications

Supporting

Mentioning

101

Contrasting

Order By: Relevance

“…FPS2 and FPS-ZM1 were detected in different samples by electrospray ionization-liquid chromatography/tandem mass spectrometry, similarly to what was reported previously (67). Briefly, the chromatography was carried out on a Prominence UFLC (Shimadzu) using a 30 mm × 2.1 mm BDS hypersil C18 column (3 micron) fitted with a hyper-select gold C18-RP (5 micron) guard column, 10 mm × 2 mm.…”

Section: Drug Measurementsmentioning

confidence: 96%

A multimodal RAGE-specific inhibitor reduces amyloid β–mediated brain disorder in a mouse model of Alzheimer disease

Deane¹,

Singh²,

Sagare³

et al. 2012

J. Clin. Invest.

504

446

View full text Add to dashboard Cite

In Alzheimer disease (AD), amyloid β peptide (Aβ) accumulates in plaques in the brain. Receptor for advanced glycation end products (RAGE) mediates Aβ-induced perturbations in cerebral vessels, neurons, and microglia in AD. Here, we identified a high-affinity RAGE-specific inhibitor (FPS-ZM1) that blocked Aβ binding to the V domain of RAGE and inhibited Aβ40-and Aβ42-induced cellular stress in RAGE-expressing cells in vitro and in the mouse brain in vivo. FPS-ZM1 was nontoxic to mice and readily crossed the blood-brain barrier (BBB). In aged APP sw/0 mice overexpressing human Aβ-precursor protein, a transgenic mouse model of AD with established Aβ pathology, FPS-ZM1 inhibited RAGE-mediated influx of circulating Aβ40 and Aβ42 into the brain. In brain, FPS-ZM1 bound exclusively to RAGE, which inhibited β-secretase activity and Aβ production and suppressed microglia activation and the neuroinflammatory response. Blockade of RAGE actions at the BBB and in the brain reduced Aβ40 and Aβ42 levels in brain markedly and normalized cognitive performance and cerebral blood flow responses in aged APP sw/0 mice. Our data suggest that FPS-ZM1 is a potent multimodal RAGE blocker that effectively controls progression of Aβ-mediated brain disorder and that it may have the potential to be a disease-modifying agent for AD.

show abstract

Section: Drug Measurementsmentioning

confidence: 96%

A multimodal RAGE-specific inhibitor reduces amyloid β–mediated brain disorder in a mouse model of Alzheimer disease

Deane¹,

Singh²,

Sagare³

et al. 2012

J. Clin. Invest.

504

446

View full text Add to dashboard Cite

show abstract

“…5), an early inhibitor resulting from medicinal chemistry optimization after a high-throughput screen, has nanomolar activity and oral bioavailability (EC 50 of 100 mgÁkg À1 for lowering of Ab levels in a transgenic mouse model) [87]. The related compound 18 (LY-411 575) even has picomolar activity and was able to lower Ab levels in transgenic mice with much lower oral dosing [97]. Similar things can be said about GSMs: medicinal chemistry efforts have turned the original NSAIDs, which displayed low activity, into compounds with nanomolar IC 50 values for lowering Ab42, such as compound 15 (Fig.…”

Section: Imp Inhibitors As Future Drugsmentioning

confidence: 99%

Intramembrane proteases as drug targets

Verhelst

2017

The FEBS Journal

View full text Add to dashboard Cite

Proteases are considered attractive drug targets. Various drugs targeting classical, soluble proteases have been approved for treatment of human disease. Intramembrane proteases (IMPs) are a more recently discovered group of proteolytic enzymes. They are embedded in lipid bilayers and their active sites are located in the plane of a membrane. All four mechanistic families of IMPs have been linked to disease, but currently, no drugs against IMPs have entered the market. In this review, I will outline the function of IMPs with a focus on the ones involved in human disease, which includes Alzheimer's disease, cancer, and infectious diseases by microorganisms. Inhibitors of IMPs are known for all mechanistic classes, but are not yet very potent or selective – aside from those targeting γ‐secretase. I will here describe the different features of IMP inhibitors and discuss a list of issues that need attention in the near future in order to improve the drug development for IMPs.

show abstract

“…One strategy that has entered the clinic is the use of a ␥-secretase inhibitor to reduce central A␤ production. Preclinically, multiple ␥-secretase inhibitors have demonstrated central and peripheral A␤-lowering activity in transgenic mouse lines overexpressing human mutant amyloid precursor protein (Dovey et al, 2001;Cirrito et al, 2003;Lanz et al, 2003Lanz et al, , 2004Wong et al, 2004;, as well as nontransgenic species (Anderson et al, 2005;Best et al, 2006;El Mouedden et al, 2006). Whereas acute treatment of old, plaque-bearing mice should have little immediate impact on plaque load (insoluble A␤), these inhibitors have been shown to inhibit A␤ in CSF (Lanz et al, 2003;Barten et al, 2005) and interstitial fluid (Cirrito et al, 2003) similarly in both plaque-free and plaque-bearing mice.…”

mentioning

confidence: 99%

Concentration-Dependent Modulation of Amyloid-β in Vivo and in Vitro Using the γ-Secretase Inhibitor, LY-450139

Lanz

Karmilowicz²,

Wood³

et al. 2006

J Pharmacol Exp Ther

Self Cite

127

View full text Add to dashboard Cite

LY-450139 is a ␥-secretase inhibitor shown to have efficacy in multiple cellular and animal models. Paradoxically, robust elevations of plasma amyloid-␤ (A␤) have been reported in dogs and humans after administration of subefficacious doses. The present study sought to further evaluate A␤ responses to LY-450139 in the guinea pig, a nontransgenic model that has an A␤ sequence identical to that of human. Male guinea pigs were treated with LY-450139 (0.2-60 mg/kg), and brain, cerebrospinal fluid, and plasma A␤ levels were characterized at 1, 3, 6, 9, and 14 h postdose. Low doses significantly elevated plasma A␤ levels at early time points, with return to baseline within hours. Higher doses inhibited A␤ levels in all compartments at early time points, but elevated plasma A␤ levels at later time points. To determine whether this phenomenon occurs under steadystate drug exposure, guinea pigs were implanted with subcutaneous minipumps delivering LY-450139 (0.3-30 mg/kg/day) for 5 days. Plasma A␤ was significantly inhibited at 10 -30 mg/kg/day, but significantly elevated at 1 mg/kg/day. To further understand the mechanism of A␤ elevation by LY-450139, H4 cells overexpressing the Swedish mutant of amyloid-precursor protein and a mouse embryonic stem cell-derived neuronal cell line were studied. In both cellular models, elevated levels of secreted A␤ were observed at subefficacious concentrations, whereas dose-responsive inhibition was observed at higher concentrations. These results suggest that LY-450139 modulates the ␥-secretase complex, eliciting A␤ lowering at high concentrations but A␤ elevation at low concentrations.The pathological accumulation of amyloid-␤ peptide into dense core plaques in the brains of Alzheimer's disease patients is the ultimate target of multiple disease-modifying drug discovery efforts. One strategy that has entered the clinic is the use of a ␥-secretase inhibitor to reduce central A␤ production. Preclinically, multiple ␥-secretase inhibitors have demonstrated central and peripheral A␤-lowering activity in transgenic mouse lines overexpressing human mutant amyloid precursor protein (Dovey et al., 2001;Cirrito et al., 2003;Lanz et al., 2003Lanz et al., , 2004Wong et al., 2004;, as well as nontransgenic species (Anderson et al., 2005;Best et al., 2006;El Mouedden et al., 2006). Whereas acute treatment of old, plaque-bearing mice should have little immediate impact on plaque load (insoluble A␤), these inhibitors have been shown to inhibit A␤ in CSF (Lanz et al., 2003;Barten et al., 2005) and interstitial fluid (Cirrito et al., 2003) similarly in both plaque-free and plaque-bearing mice. In addition, plasma A␤ has been shown to be reduced similarly by ␥-secretase inhibition in both young and old Tg2576 mice (Lanz et al., 2003;Barten et al., 2005). These findings indicate that despite the presence or absence of insoluble A␤ plaques, these compounds had similar potency in reducing soluble, secreted A␤ in young and old transgenic mice.The ability of plasma and CSF A␤ to track pharmacologic...

show abstract

Studies of Aβ Pharmacodynamics in the Brain, Cerebrospinal Fluid, and Plasma in Young (Plaque-Free) Tg2576 Mice Using the γ-Secretase Inhibitor N²-[(2S)-2-(3,5-Difluorophenyl)-2-hydroxyethanoyl]-N¹-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY-411575)

Cited by 131 publications

References 22 publications

A multimodal RAGE-specific inhibitor reduces amyloid β–mediated brain disorder in a mouse model of Alzheimer disease

A multimodal RAGE-specific inhibitor reduces amyloid β–mediated brain disorder in a mouse model of Alzheimer disease

Intramembrane proteases as drug targets

Concentration-Dependent Modulation of Amyloid-β in Vivo and in Vitro Using the γ-Secretase Inhibitor, LY-450139

Contact Info

Product

Resources

About