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19 results on '"Sonnenberg-Reines, June"'

1. Synthesis and structure–activity relationship of a novel series of heterocyclic sulfonamide γ-secretase inhibitors

Author

Pu, Jun, Kreft, Anthony F., Aschmies, Suzan H., Atchison, Kevin P., Berkowitz, Joshua, Caggiano, Thomas J., Chlenov, Micheal, Diamantidis, George, Harrison, Boyd L., Hu, Yun, Huryn, Donna, Steven Jacobsen, J., Jin, Mei, Lipinski, Kerri, Lu, Peimin, Martone, Robert L., Morris, Koi, Sonnenberg-Reines, June, Riddell, Dave R., Sabalski, Joan, Sun, Shaiu-Ching, Wagner, Erik, Wang, Yiqun, Xu, Zheng, Zhou, Hua, and Resnick, Lynn

Published
2009
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6. ( S) -N-(5-Chlorothiophene-2-sulfonyl)-β,β-diethylalaninol a Notch-1-sparing γ-secretase inhibitor

Author

Cole, Derek C., Stock, Joseph R., Kreft, Anthony F., Antane, Madelene, Aschmies, Suzan H., Atchison, Kevin P., Casebier, David S., Comery, Thomas A., Diamantidis, George, Ellingboe, John W., Harrison, Boyd L., Hu, Yun, Jin, Mei, Kubrak, Dennis M., Lu, Peimin, Mann, Charles W., Martone, Robert L., Moore, William J., Oganesian, Aram, Riddell, David R., Sonnenberg-Reines, June, Sun, Shaiu-Ching, Wagner, Erik, Wang, Zheng, Woller, Kevin R., Xu, Zheng, Zhou, Hua, and Jacobsen, J. Steven

Published
2009
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7. Discovery of a novel series of Notch-sparing γ-secretase inhibitors

Author

Kreft, Anthony, Harrison, Boyd, Aschmies, Suzan, Atchison, Kevin, Casebier, David, Cole, Derek C., Diamantidis, George, Ellingboe, John, Hauze, Diane, Hu, Yun, Huryn, Donna, Jin, Mei, Kubrak, Dennis, Lu, Peimin, Lundquist, Joseph, Mann, Charles, Martone, Robert, Moore, William, Oganesian, Aram, Porte, Alex, Riddell, Dave R., Sonnenberg-Reines, June, Stock, Joseph R., Sun, Shaiu-Ching, Wagner, Erik, Woller, Kevin, Xu, Zheng, Zhou, Hua, and Steven Jacobsen, J.

Published
2008
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8. Begacestat (GSI-953): A Novel, Selective Thiophene Sulfonamide Inhibitor of Amyloid Precursor Protein γ-Secretase for the Treatment of Alzheimer's Disease

Author

Martone, Robert L., primary, Zhou, Hua, additional, Atchison, Kevin, additional, Comery, Thomas, additional, Xu, Jane Z., additional, Huang, Xinyi, additional, Gong, Xioahai, additional, Jin, Mei, additional, Kreft, Anthony, additional, Harrison, Boyd, additional, Mayer, Scott C., additional, Aschmies, Suzan, additional, Gonzales, Cathleen, additional, Zaleska, Margaret M., additional, Riddell, David R., additional, Wagner, Erik, additional, Lu, Peimin, additional, Sun, Shaiu-Ching, additional, Sonnenberg-Reines, June, additional, Oganesian, Aram, additional, Adkins, Karissa, additional, Leach, Michael W., additional, Clarke, David W., additional, Huryn, Donna, additional, Abou-Gharbia, Magid, additional, Magolda, Ronald, additional, Bard, Jonathan, additional, Frick, Glen, additional, Raje, Sangeeta, additional, Forlow, S. Bradley, additional, Balliet, Carrie, additional, Burczynski, Michael E., additional, Reinhart, Peter H., additional, Wan, Hong I., additional, Pangalos, Menelas N., additional, and Jacobsen, J. Steven, additional

Published
2009
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9. Discovery of Begacestat, a Notch-1-Sparing γ-Secretase Inhibitor for the Treatment of Alzheimer’s Disease

Author

Mayer, Scott C., primary, Kreft, Anthony F., additional, Harrison, Boyd, additional, Abou-Gharbia, Magid, additional, Antane, Madelene, additional, Aschmies, Suzan, additional, Atchison, Kevin, additional, Chlenov, Michael, additional, Cole, Derek C., additional, Comery, Thomas, additional, Diamantidis, George, additional, Ellingboe, John, additional, Fan, Kristi, additional, Galante, Rocco, additional, Gonzales, Cathleen, additional, Ho, Douglas M., additional, Hoke, Molly E., additional, Hu, Yun, additional, Huryn, Donna, additional, Jain, Uday, additional, Jin, Mei, additional, Kremer, Kenneth, additional, Kubrak, Dennis, additional, Lin, Melissa, additional, Lu, Peimin, additional, Magolda, Ron, additional, Martone, Robert, additional, Moore, William, additional, Oganesian, Aram, additional, Pangalos, Menelas N., additional, Porte, Alex, additional, Reinhart, Peter, additional, Resnick, Lynn, additional, Riddell, David R., additional, Sonnenberg-Reines, June, additional, Stock, Joseph R., additional, Sun, Shaiu-Ching, additional, Wagner, Erik, additional, Wang, Ting, additional, Woller, Kevin, additional, Xu, Zheng, additional, Zaleska, Margaret M., additional, Zeldis, Joseph, additional, Zhang, Minsheng, additional, Zhou, Hua, additional, and Jacobsen, J. Steven, additional

Published
2008
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10. P2-302: GSI-953 is a potent APP-selective gamma-secretase inhibitor for the treatment of Alzheimer's disease

Author

Jacobsen, Steven, primary, Comery, Thomas, additional, Aschmies, Suzan, additional, Zhou, Hua, additional, Jin, Mei, additional, Atchison, Kevin, additional, Xu, Jane, additional, Wagner, Erik, additional, Sonnenberg-Reines, June, additional, Kreft, Anthony, additional, Sun, Roy, additional, Liu, Peimin, additional, Gong, Xiaohai, additional, Zaleska, Margaret, additional, Adkins, Karissa, additional, Oganesian, Aram, additional, Folletti, Maximillian, additional, Wan, Hong, additional, Mayer, Scott, additional, Hoke, Molly, additional, Reinhart, Peter, additional, Harrison, Boyd, additional, Magolda, Ron, additional, Pangalos, Menelas, additional, and Martone, Robert, additional

Published
2008
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11. P4-244: Discovery of a novel series of notch-sparing γ-secretase inhibitors

Author

Harrison, Boyd L., primary, Kreft, Anthony, additional, Aschmies, Susan, additional, Atchison, Kevin, additional, Cole, Derek, additional, Ellingboe, John, additional, Hauze, Diane, additional, Hu, Yun, additional, Huryn, Donna, additional, Jin, Mei, additional, Kubrak, Dennis, additional, Lu, Peimin, additional, Mann, Charles, additional, Martone, Robert, additional, Moore, William, additional, Porte, Alex, additional, Riddell, David, additional, Sonnenberg-Reines, June, additional, Stock, Joseph, additional, Sun, Shaiu-Ching, additional, Wagner, Erik, additional, Woller, Kevin, additional, Xu, Zheng, additional, Zhou, Hua, additional, and Jacobsen, Steven, additional

Published
2006
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12. Acute γ-Secretase Inhibition Improves Contextual Fear Conditioning in the Tg2576 Mouse Model of Alzheimer's Disease

Author

Comery, Thomas A., primary, Martone, Robert L., additional, Aschmies, Suzan, additional, Atchison, Kevin P., additional, Diamantidis, George, additional, Gong, Xiaohai, additional, Zhou, Hua, additional, Kreft, Anthony F., additional, Pangalos, Menelas N., additional, Sonnenberg-Reines, June, additional, Jacobsen, J. Steven, additional, and Marquis, Karen L., additional

Published
2005
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16. Begacestat (GSI-953): a novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase for the treatment of Alzheimer's disease.

Author

Martone, Robert L, Zhou, Hua, Atchison, Kevin, Comery, Thomas, Xu, Jane Z, Huang, Xinyi, Gong, Xioahai, Jin, Mei, Kreft, Anthony, Harrison, Boyd, Mayer, Scott C, Aschmies, Suzan, Gonzales, Cathleen, Zaleska, Margaret M, Riddell, David R, Wagner, Erik, Lu, Peimin, Sun, Shaiu-Ching, Sonnenberg-Reines, June, Oganesian, Aram, Adkins, Karissa, Leach, Michael W, Clarke, David W, Huryn, Donna, Abou-Gharbia, Magid, Magolda, Ronald, Bard, Jonathan, Frick, Glen, Raje, Sangeeta, Forlow, S Bradley, Balliet, Carrie, Burczynski, Michael E, Reinhart, Peter H, Wan, Hong I, Pangalos, Menelas N, and Jacobsen, J Steven

Abstract

The presenilin containing gamma-secretase complex is responsible for the regulated intramembraneous proteolysis of the amyloid precursor protein (APP), the Notch receptor, and a multitude of other substrates. gamma-Secretase catalyzes the final step in the generation of Abeta(40) and Abeta(42) peptides from APP. Amyloid beta-peptides (Abeta peptides) aggregate to form neurotoxic oligomers, senile plaques, and congophilic angiopathy, some of the cardinal pathologies associated with Alzheimer's disease. Although inhibition of this protease acting on APP may result in potentially therapeutic reductions of neurotoxic Abeta peptides, nonselective inhibition of the enzyme may cause severe adverse events as a result of impaired Notch receptor processing. Here, we report the preclinical pharmacological profile of GSI-953 (begacestat), a novel thiophene sulfonamide gamma-secretase inhibitor (GSI) that selectively inhibits cleavage of APP over Notch. This GSI inhibits Abeta production with low nanomolar potency in cellular and cell-free assays of gamma-secretase function, and displaces a tritiated analog of GSI-953 from enriched gamma-secretase enzyme complexes with similar potency. Cellular assays of Notch cleavage reveal that this compound is approximately 16-fold selective for the inhibition of APP cleavage. In the human APP-overexpressing Tg2576 transgenic mouse, treatment with this orally active compound results in a robust reduction in brain, plasma, and cerebral spinal fluid Abeta levels, and a reversal of contextual fear-conditioning deficits that are correlated with Abeta load. In healthy human volunteers, oral administration of a single dose of GSI-953 produces dose-dependent changes in plasma Abeta levels, confirming pharmacodynamic activity of GSI-953 in humans.

Published
2009
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17. Discovery of begacestat, a Notch-1-sparing gamma-secretase inhibitor for the treatment of Alzheimer's disease.

Author

Mayer SC, Kreft AF, Harrison B, Abou-Gharbia M, Antane M, Aschmies S, Atchison K, Chlenov M, Cole DC, Comery T, Diamantidis G, Ellingboe J, Fan K, Galante R, Gonzales C, Ho DM, Hoke ME, Hu Y, Huryn D, Jain U, Jin M, Kremer K, Kubrak D, Lin M, Lu P, Magolda R, Martone R, Moore W, Oganesian A, Pangalos MN, Porte A, Reinhart P, Resnick L, Riddell DR, Sonnenberg-Reines J, Stock JR, Sun SC, Wagner E, Wang T, Woller K, Xu Z, Zaleska MM, Zeldis J, Zhang M, Zhou H, and Jacobsen JS

Subjects
Alzheimer Disease enzymology, Amyloid Precursor Protein Secretases metabolism, Amyloid beta-Peptides metabolism, Animals, Crystallography, X-Ray, Disease Models, Animal, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Mice, Mice, Transgenic, Models, Molecular, Molecular Conformation, Stereoisomerism, Structure-Activity Relationship, Sulfonamides chemical synthesis, Sulfonamides chemistry, Thiophenes chemical synthesis, Thiophenes chemistry, Alzheimer Disease drug therapy, Amyloid Precursor Protein Secretases antagonists & inhibitors, Drug Discovery, Enzyme Inhibitors pharmacology, Receptor, Notch1 metabolism, Sulfonamides pharmacology, Thiophenes pharmacology
Abstract

SAR on HTS hits 1 and 2 led to the potent, Notch-1-sparing GSI 9, which lowered brain Abeta in Tg2576 mice at 100 mg/kg po. Converting the metabolically labile methyl groups in 9 to trifluoromethyl groups afforded the more stable analogue 10, which had improved in vivo potency. Further side chain modification afforded the potent Notch-1-sparing GSI begacestat (5), which was selected for development for the treatment of Alzheimer's disease.

Published
2008
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18. Acute gamma-secretase inhibition improves contextual fear conditioning in the Tg2576 mouse model of Alzheimer's disease.

Author

Comery TA, Martone RL, Aschmies S, Atchison KP, Diamantidis G, Gong X, Zhou H, Kreft AF, Pangalos MN, Sonnenberg-Reines J, Jacobsen JS, and Marquis KL

Subjects
3',5'-Cyclic-AMP Phosphodiesterases antagonists & inhibitors, Aging psychology, Alzheimer Disease genetics, Amyloid Precursor Protein Secretases, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor genetics, Amyloid beta-Protein Precursor metabolism, Animals, Aspartic Acid Endopeptidases, Cognition drug effects, Cognition Disorders chemically induced, Cognition Disorders psychology, Cyclic Nucleotide Phosphodiesterases, Type 4, Disease Models, Animal, Mice, Mice, Transgenic, Mutation, Phosphodiesterase Inhibitors pharmacology, Rolipram pharmacology, Triglycerides pharmacology, gamma-Aminobutyric Acid analogs & derivatives, gamma-Aminobutyric Acid pharmacology, Alzheimer Disease metabolism, Alzheimer Disease psychology, Conditioning, Psychological drug effects, Endopeptidases metabolism, Enzyme Inhibitors pharmacology, Fear
Abstract

Transgenic mice (Tg2576) overexpressing the Swedish mutation of the human amyloid precursor protein display biochemical, pathological, and behavioral markers consistent with many aspects of Alzheimer's disease, including impaired hippocampal function. Impaired, hippocampal-dependent, contextual fear conditioning (CFC) is observed in mice as young as 20 weeks of age. This impairment can be attenuated after treatment before training with the phosphodiesterase-4 inhibitor rolipram (0.1 mg/kg, i.p.). A rolipram-associated improvement is also observed in the littermate controls, suggesting that the effect of rolipram is independent of beta-amyloid. Acute treatment before training (but not after training or before testing) with the gamma-secretase inhibitor (GSI) N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine-t-butylester (DAPT), at a dose that reduces brain concentrations of beta-amyloid (100 mg/kg), attenuates the impairment in 20- to 65-week-old Tg2576 mice. Importantly, DAPT had no effect on performance of control littermates. These data are supportive of a role of beta-amyloid in the impairment of CFC in Tg2576 mice. Furthermore, they suggest that acute treatment with GSI may provide improved cognitive functioning as well as disease-modifying effects in Alzheimer's disease.

Published
2005
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19. Molecular-modeling based design, synthesis, and activity of substituted piperidines as gamma-secretase inhibitors.

Author

Gundersen E, Fan K, Haas K, Huryn D, Steven Jacobsen J, Kreft A, Martone R, Mayer S, Sonnenberg-Reines J, Sun SC, and Zhou H

Subjects
Alzheimer Disease enzymology, Amyloid Precursor Protein Secretases, Animals, Brain metabolism, Drug Design, Endopeptidases metabolism, Models, Molecular, Piperidines pharmacology, Protease Inhibitors pharmacology, Protein Binding, Structure-Activity Relationship, Amyloid beta-Peptides antagonists & inhibitors, Brain drug effects, Endopeptidases drug effects, Piperidines chemical synthesis, Protease Inhibitors chemical synthesis
Abstract

Alzheimer's disease (AD) is a debilitating disease widely thought to be associated with the accumulation of beta amyloid (Abeta) in the brain. Inhibition of gamma-secretase, one of the enzymes responsible for Abeta production, may be a useful strategy for the treatment of AD. Described below is a series of gamma-secretase inhibitors designed from a scaffold identified by a ROCS [J. Comput. Chem.1996, 17, 1653] search of the corporate database.

Published
2005
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