Erik Wagner - Academia.edu (original) (raw)
Papers by Erik Wagner
![Research paper thumbnail of Discovery and initial optimization of 5, 5'-disubstituted aminohydantoins as potent [beta]-secretase (BACE1) inhibitors](https://attachments.academia-assets.com/74465206/thumbnails/1.jpg)
](Bioorganic & medicinal …, 2010
Alzheimer's disease (AD) is a progressive neurodegenerative disease that is the leading caus... more Alzheimer's disease (AD) is a progressive neurodegenerative disease that is the leading cause of long-term decline in cognitive function in the elderly. It is estimated that more than 27 million people worldwide have AD and the number of cases is likely to increase in the future. 1 ...
Journal of medicinal …, 2009
The identification of small molecule aminoimidazoles as potent and selective human β-secretase in... more The identification of small molecule aminoimidazoles as potent and selective human β-secretase inhibitors is reported. These analogues demonstrate low nannomolar potency for BACE1 in a FRET assay, exhibit comparable activity in a cell-based (ELISA) assay, and show >100× ...
Journal of medicinal …, 2006
Like other aspartic proteases, 20-23 BACE1 consists of two structural domains, the N-and C-termin... more Like other aspartic proteases, 20-23 BACE1 consists of two structural domains, the N-and C-terminus, which constitute the active site and a β-hairpin loop which forms the flap region. The flap opens to allow the substrate to enter and then closes down on the substrate ...
Salmon calcitonin (sCT) is a therapeutic peptide used in the treatment of Paget's Disease, postme... more Salmon calcitonin (sCT) is a therapeutic peptide used in the treatment of Paget's Disease, postmenopausal osteoporosis, and hypercalcemia due to malignancy. In this study, recombinant sCT (rsCT) was administered intravenously (iv), subcutaneously (sc), and intraduodenally (id.) in rats to evaluate pharmacodynamic (PD) response as a measure of rsCT bioavailability (F) and to test the feasibility of delivering rsCT orally. rsCT pharmacokinetics were linear throughout the range of iv and sc doses studied. Following sc administration, Franged from 11.2% to 23.1% and was linear. The absorption of rsCT after id. administration was low (0.022%); however, a significant lowering of serum calcium concentrations was observed. Serum calcium lowering was nonlinear and saturable after sc administration with the minimum dose required for maximum calcium lowering (Dmln/max) equal to 10.2 ng and a maximal response of 426.8 mg minidl. Using Dmln/max as the reference dose, absolute Fs were recalculated using PD response after id. administration of 1 and 2 mg of rsCT and were 0.040% and 0.029%, respectively. Substantial overestimates of F were obtained when the reference dose was not properly selected. While the absorption of rsCT was low, the significant lowering of serum calcium levels suggests that oral delivery of sCT is feasible. The results of these studies also suggest that PD response is useful in assessing the oral bioavailability of peptides; however, when PD response is saturable, as is the case for rsCT, the reference dose should be carefully selected in order to avoid overestimates of F.
Bioorganic & medicinal …, 2008
Proteolytic cleavage of amyloid precursor protein by β-secretase (BACE-1) and γ-secretase leads t... more Proteolytic cleavage of amyloid precursor protein by β-secretase (BACE-1) and γ-secretase leads to formation of β-amyloid (Aβ) a key component of amyloid plaques, which are considered the hallmark of Alzheimer's disease. Small molecule inhibitors of BACE-1 may reduce levels ...
Journal of medicinal …, 2008
Not only is 9 a potent GSI but it also has promising Notch-1-sparing selectivity (10-fold). This ... more Not only is 9 a potent GSI but it also has promising Notch-1-sparing selectivity (10-fold). This compound was profiled for in vivo reduction of brain Aβ 40 and Aβ 42 in the Tg2576 mouse model at the 4 h time point when given 100 mg/kg po. Brain Aβ 40 and Aβ 42 in the Tg2576 ...
European journal of …, 2000
The dose-dependent disposition, ®rst pass hepatic elimination, and absorption pharmacokinetics (P... more The dose-dependent disposition, ®rst pass hepatic elimination, and absorption pharmacokinetics (PK) of salmon calcitonin (sCT) were investigated in a canine Intestinal Vascular Access Port (IVAP) model. The PK of sCT were determined after intravenous (IV), subcutaneous (SC), portal venous (PV), and oral (PO) administration of sCT. Regional oral absorption of unformulated sCT was also evaluated by direct administration into the duodenum (ID), ileum (IL), and colon (IC) by means of surgically implanted, chronic catheters. Plasma samples were collected and analyzed by radioimmunoassay (RIA). Salmon calcitonin PK were evaluated using 2-compartmental and model independent methods. Intravenous sCT PK were non-linear over the dose range studied. High dose groups (100±1000 mg) demonstrated higher total plasma clearance (CL) and V dss than the low dose groups (1±25 mg). However, the MRT did not change for doses ranging from 10 to 1000 mg. After SC administration, the absorption of sCT was rapid with bioavailability (BA) varying from 21.4 to 52.9%. However, the BA of sCT was low after ID, IL, and IC administration (0.039, 0.064, and 0.021%, respectively). The role of hepatic ®rst-pass elimination was negligible. The results of these studies demonstrate that the elimination of sCT is rapid but does not occur in the liver. Enhanced sCT clearance at higher doses was indicated by increasing V dss values, and it is hypothesized that increased renal blood¯ow and/or saturated plasma protein binding may contribute to the non-linear behavior. The IVAP canine model was found to have utility for probing the absorption and disposition PK of sCT. The combination of high oral bioavailability variability and non-linear disposition of sCT may produce highly variable therapeutic effects. The practical impact of the non-linear disposition of sCT remains to be determined. Based on the current results it appears that the rate-limiting step to the successful oral administration of sCT is its delivery into the portal vein since hepatic metabolism was negligible.
Alzheimer's & Dementia, 2009
… of Pharmacology and …, 2009
The presenilin containing γ-secretase complex is responsible for the regulated intramembraneous p... more The presenilin containing γ-secretase complex is responsible for the regulated intramembraneous proteolysis of the amyloid precursor protein (APP), the Notch receptor, and a multitude of other substrates. γ-Secretase catalyzes the final step in the generation of Aβ 40 and Aβ 42 ...
Bioorganic & medicinal …, 2010
Alzheimer's disease (AD) is a progressive neurodegenerative disease that is the leading caus... more Alzheimer's disease (AD) is a progressive neurodegenerative disease that is the leading cause of long-term decline in cognitive function in the elderly. It is estimated that more than 27 million people worldwide have AD and the number of cases is likely to increase in the future. 1 ...
Journal of medicinal …, 2009
The identification of small molecule aminoimidazoles as potent and selective human β-secretase in... more The identification of small molecule aminoimidazoles as potent and selective human β-secretase inhibitors is reported. These analogues demonstrate low nannomolar potency for BACE1 in a FRET assay, exhibit comparable activity in a cell-based (ELISA) assay, and show >100× ...
Journal of medicinal …, 2006
Like other aspartic proteases, 20-23 BACE1 consists of two structural domains, the N-and C-termin... more Like other aspartic proteases, 20-23 BACE1 consists of two structural domains, the N-and C-terminus, which constitute the active site and a β-hairpin loop which forms the flap region. The flap opens to allow the substrate to enter and then closes down on the substrate ...
Salmon calcitonin (sCT) is a therapeutic peptide used in the treatment of Paget's Disease, postme... more Salmon calcitonin (sCT) is a therapeutic peptide used in the treatment of Paget's Disease, postmenopausal osteoporosis, and hypercalcemia due to malignancy. In this study, recombinant sCT (rsCT) was administered intravenously (iv), subcutaneously (sc), and intraduodenally (id.) in rats to evaluate pharmacodynamic (PD) response as a measure of rsCT bioavailability (F) and to test the feasibility of delivering rsCT orally. rsCT pharmacokinetics were linear throughout the range of iv and sc doses studied. Following sc administration, Franged from 11.2% to 23.1% and was linear. The absorption of rsCT after id. administration was low (0.022%); however, a significant lowering of serum calcium concentrations was observed. Serum calcium lowering was nonlinear and saturable after sc administration with the minimum dose required for maximum calcium lowering (Dmln/max) equal to 10.2 ng and a maximal response of 426.8 mg minidl. Using Dmln/max as the reference dose, absolute Fs were recalculated using PD response after id. administration of 1 and 2 mg of rsCT and were 0.040% and 0.029%, respectively. Substantial overestimates of F were obtained when the reference dose was not properly selected. While the absorption of rsCT was low, the significant lowering of serum calcium levels suggests that oral delivery of sCT is feasible. The results of these studies also suggest that PD response is useful in assessing the oral bioavailability of peptides; however, when PD response is saturable, as is the case for rsCT, the reference dose should be carefully selected in order to avoid overestimates of F.
Bioorganic & medicinal …, 2008
Proteolytic cleavage of amyloid precursor protein by β-secretase (BACE-1) and γ-secretase leads t... more Proteolytic cleavage of amyloid precursor protein by β-secretase (BACE-1) and γ-secretase leads to formation of β-amyloid (Aβ) a key component of amyloid plaques, which are considered the hallmark of Alzheimer's disease. Small molecule inhibitors of BACE-1 may reduce levels ...
Journal of medicinal …, 2008
Not only is 9 a potent GSI but it also has promising Notch-1-sparing selectivity (10-fold). This ... more Not only is 9 a potent GSI but it also has promising Notch-1-sparing selectivity (10-fold). This compound was profiled for in vivo reduction of brain Aβ 40 and Aβ 42 in the Tg2576 mouse model at the 4 h time point when given 100 mg/kg po. Brain Aβ 40 and Aβ 42 in the Tg2576 ...
European journal of …, 2000
The dose-dependent disposition, ®rst pass hepatic elimination, and absorption pharmacokinetics (P... more The dose-dependent disposition, ®rst pass hepatic elimination, and absorption pharmacokinetics (PK) of salmon calcitonin (sCT) were investigated in a canine Intestinal Vascular Access Port (IVAP) model. The PK of sCT were determined after intravenous (IV), subcutaneous (SC), portal venous (PV), and oral (PO) administration of sCT. Regional oral absorption of unformulated sCT was also evaluated by direct administration into the duodenum (ID), ileum (IL), and colon (IC) by means of surgically implanted, chronic catheters. Plasma samples were collected and analyzed by radioimmunoassay (RIA). Salmon calcitonin PK were evaluated using 2-compartmental and model independent methods. Intravenous sCT PK were non-linear over the dose range studied. High dose groups (100±1000 mg) demonstrated higher total plasma clearance (CL) and V dss than the low dose groups (1±25 mg). However, the MRT did not change for doses ranging from 10 to 1000 mg. After SC administration, the absorption of sCT was rapid with bioavailability (BA) varying from 21.4 to 52.9%. However, the BA of sCT was low after ID, IL, and IC administration (0.039, 0.064, and 0.021%, respectively). The role of hepatic ®rst-pass elimination was negligible. The results of these studies demonstrate that the elimination of sCT is rapid but does not occur in the liver. Enhanced sCT clearance at higher doses was indicated by increasing V dss values, and it is hypothesized that increased renal blood¯ow and/or saturated plasma protein binding may contribute to the non-linear behavior. The IVAP canine model was found to have utility for probing the absorption and disposition PK of sCT. The combination of high oral bioavailability variability and non-linear disposition of sCT may produce highly variable therapeutic effects. The practical impact of the non-linear disposition of sCT remains to be determined. Based on the current results it appears that the rate-limiting step to the successful oral administration of sCT is its delivery into the portal vein since hepatic metabolism was negligible.
Alzheimer's & Dementia, 2009
… of Pharmacology and …, 2009
The presenilin containing γ-secretase complex is responsible for the regulated intramembraneous p... more The presenilin containing γ-secretase complex is responsible for the regulated intramembraneous proteolysis of the amyloid precursor protein (APP), the Notch receptor, and a multitude of other substrates. γ-Secretase catalyzes the final step in the generation of Aβ 40 and Aβ 42 ...