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22 results on '"Chambers, Mark"'

1. Identification and Optimization of RNA-Splicing Modulators as Huntingtin Protein-Lowering Agents for the Treatment of Huntington’s Disease

Author

Liu, Longbin, primary, Malagu, Karine, additional, Haughan, Alan F., additional, Khetarpal, Vinod, additional, Stott, Andrew J., additional, Esmieu, William, additional, Vater, Huw D., additional, Webster, Stephen J., additional, Van de Poël, Amanda J., additional, Clissold, Cole, additional, Cosgrove, Brett, additional, Sutton, Benjamin, additional, Spencer, Jonathan A., additional, Breccia, Perla, additional, Gancia, Emanuela, additional, Bonomo, Silvia, additional, Ladduwahetty, Tammy, additional, Lazari, Ovadia, additional, Patel, Hiral, additional, Atton, Helen C., additional, Clifton, Steve, additional, Mota, Daniel M., additional, Magnani, Dario, additional, O’Neill, Amy, additional, Stebbeds, Marta, additional, Macabuag, Natsuko, additional, Todd, Daniel, additional, Herva, Maria E., additional, Mitchell, Philip, additional, Visser, Mijke, additional, Compte Sancerni, Sara, additional, Grand Moursel, Laure, additional, da Silva, Marta, additional, Kritikou, Eva, additional, Heikkinen, Taneli T., additional, Bolkvadze, Tamuna, additional, Fodale, Valentina, additional, Spadafora, Debora, additional, Daldin, Manuel, additional, Bresciani, Alberto, additional, Mangette, John E., additional, Doherty, Elizabeth M., additional, Lee, Matthew R., additional, Herbst, Todd, additional, Monteagudo, Edith, additional, Macdonald, Douglas, additional, Plotnikov, Nikolay V., additional, Chambers, Mark, additional, McAllister, George, additional, Muňoz-Sanjuan, Ignacio, additional, and Dominguez, Celia, additional

Published
2023
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2. Defining Target Engagement Required for Efficacy In Vivo at the Retinoic Acid Receptor-Related Orphan Receptor C2 (RORγt)

Author

Lugar, Charles W., primary, Clarke, Christian A., additional, Morphy, Richard, additional, Rudyk, Helene, additional, Sapmaz, Selma, additional, Stites, Ryan E., additional, Vaught, Grant M., additional, Furness, Kelly, additional, Broughton, Howard B., additional, Durst, Greg L., additional, Clawson, David K., additional, Stout, Stephanie L., additional, Guo, Sherry Y., additional, Durbin, Jim D., additional, Stayrook, Keith R., additional, Edmondson, Denise D., additional, Kikly, Kristy, additional, New, Nicole E., additional, Bina, Holly A., additional, Chambers, Mark G., additional, Shetler, Pamela, additional, Chang, William Y., additional, Chang, Veavi Ching-Yun, additional, Barr, Rob, additional, Gough, Wendy H., additional, Steele, Jimmy P., additional, Getman, Brian, additional, Patel, Nita, additional, Mathes, Brian M., additional, and Richardson, Timothy I., additional

Published
2021
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3. Defining Target Engagement Required for Efficacy In Vivoat the Retinoic Acid Receptor-Related Orphan Receptor C2 (RORγt)

Author

Lugar, Charles W., Clarke, Christian A., Morphy, Richard, Rudyk, Helene, Sapmaz, Selma, Stites, Ryan E., Vaught, Grant M., Furness, Kelly, Broughton, Howard B., Durst, Greg L., Clawson, David K., Stout, Stephanie L., Guo, Sherry Y., Durbin, Jim D., Stayrook, Keith R., Edmondson, Denise D., Kikly, Kristy, New, Nicole E., Bina, Holly A., Chambers, Mark G., Shetler, Pamela, Chang, William Y., Chang, Veavi Ching-Yun, Barr, Rob, Gough, Wendy H., Steele, Jimmy P., Getman, Brian, Patel, Nita, Mathes, Brian M., and Richardson, Timothy I.

Abstract

The Th17 pathway has been implicated in autoimmune diseases. The retinoic acid receptor-related orphan receptor C2 (RORγt) is a master regulator of Th17 cells and controls the expression of IL-17A. RORγt is expressed primarily in IL-17A-producing lymphoid cells. Here we describe a virtual screen of the ligand-binding pocket and subsequent screen in a binding assay that identified the 1-benzyl-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]-2′-carboxamide scaffold as a starting point for optimization of binding affinity and functional activity guided by structure-based design. Compound 12demonstrated activity in a mouse PK/PD model and efficacy in an inflammatory arthritis mouse model that were used to define the level and duration of target engagement required for efficacy in vivo. Further optimization to improve ADME and physicochemical properties with guidance from simulations and modeling provided compound 22, which is projected to achieve the level and duration of target engagement required for efficacy in the clinic.

Published
2021
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5. Use of Osmotic Pumps to Establish the Pharmacokinetic–Pharmacodynamic Relationship and Define Desirable Human Performance Characteristics for Aggrecanase Inhibitors

Author

Wiley, Michael R., primary, Durham, Timothy B., additional, Adams, Lisa A., additional, Chambers, Mark G., additional, Lin, Chaohua, additional, Liu, Chin, additional, Marimuthu, Jothirajah, additional, Mitchell, Peter G., additional, Mudra, Daniel R., additional, Swearingen, Craig A., additional, Toth, James L., additional, Weller, Jennifer M., additional, and Thirunavukkarasu, Kannan, additional

Published
2016
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6. Identification of Potent and Selective Hydantoin Inhibitors of Aggrecanase-1 and Aggrecanase-2 That Are Efficacious in Both Chemical and Surgical Models of Osteoarthritis

Author

Durham, Timothy B., primary, Klimkowski, Valentine J., additional, Rito, Christopher J., additional, Marimuthu, Jothirajah, additional, Toth, James L., additional, Liu, Chin, additional, Durbin, Jim D., additional, Stout, Stephanie L., additional, Adams, Lisa, additional, Swearingen, Craig, additional, Lin, Chaohua, additional, Chambers, Mark G., additional, Thirunavukkarasu, Kannan, additional, and Wiley, Michael R., additional

Published
2014
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7. Discovery of Highly Potent, Selective, and Brain-Penetrant Aminopyrazole Leucine-Rich Repeat Kinase 2 (LRRK2) Small Molecule Inhibitors

Author

Estrada, Anthony A., primary, Chan, Bryan K., additional, Baker-Glenn, Charles, additional, Beresford, Alan, additional, Burdick, Daniel J., additional, Chambers, Mark, additional, Chen, Huifen, additional, Dominguez, Sara L., additional, Dotson, Jennafer, additional, Drummond, Jason, additional, Flagella, Michael, additional, Fuji, Reina, additional, Gill, Andrew, additional, Halladay, Jason, additional, Harris, Seth F., additional, Heffron, Timothy P., additional, Kleinheinz, Tracy, additional, Lee, Donna W., additional, Pichon, Claire E. Le, additional, Liu, Xingrong, additional, Lyssikatos, Joseph P., additional, Medhurst, Andrew D., additional, Moffat, John G., additional, Nash, Kevin, additional, Scearce-Levie, Kimberly, additional, Sheng, Zejuan, additional, Shore, Daniel G., additional, Wong, Susan, additional, Zhang, Shuo, additional, Zhang, Xiaolin, additional, Zhu, Haitao, additional, and Sweeney, Zachary K., additional

Published
2014
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8. Selective Cannabinoid Receptor Type 2 (CB2) Agonists: Optimization of a Series of Purines Leading to the Identification of a Clinical Candidate for the Treatment of Osteoarthritic Pain

Author

Hollinshead, Sean P., primary, Tidwell, Michael W., additional, Palmer, John, additional, Guidetti, Rossella, additional, Sanderson, Adam, additional, Johnson, Michael P., additional, Chambers, Mark G., additional, Oskins, Jennifer, additional, Stratford, Robert, additional, and Astles, Peter C., additional

Published
2013
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9. Discovery of Highly Potent, Selective, and Brain-Penetrable Leucine-Rich Repeat Kinase 2 (LRRK2) Small Molecule Inhibitors

Author

Estrada, Anthony A., primary, Liu, Xingrong, additional, Baker-Glenn, Charles, additional, Beresford, Alan, additional, Burdick, Daniel J., additional, Chambers, Mark, additional, Chan, Bryan K., additional, Chen, Huifen, additional, Ding, Xiao, additional, DiPasquale, Antonio G., additional, Dominguez, Sara L., additional, Dotson, Jennafer, additional, Drummond, Jason, additional, Flagella, Michael, additional, Flynn, Sean, additional, Fuji, Reina, additional, Gill, Andrew, additional, Gunzner-Toste, Janet, additional, Harris, Seth F., additional, Heffron, Timothy P., additional, Kleinheinz, Tracy, additional, Lee, Donna W., additional, Le Pichon, Claire E., additional, Lyssikatos, Joseph P., additional, Medhurst, Andrew D., additional, Moffat, John G., additional, Mukund, Susmith, additional, Nash, Kevin, additional, Scearce-Levie, Kimberly, additional, Sheng, Zejuan, additional, Shore, Daniel G., additional, Tran, Thuy, additional, Trivedi, Naimisha, additional, Wang, Shumei, additional, Zhang, Shuo, additional, Zhang, Xiaolin, additional, Zhao, Guiling, additional, Zhu, Haitao, additional, and Sweeney, Zachary K., additional

Published
2012
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11. An Orally Bioavailable, Functionally Selective Inverse Agonist at the Benzodiazepine Site of GABAA α5 Receptors with Cognition Enhancing Properties

Author

Chambers, Mark S., primary, Atack, John R., additional, Carling, Robert W., additional, Collinson, Neil, additional, Cook, Susan M., additional, Dawson, Gerard R., additional, Ferris, Pushpindar, additional, Hobbs, Sarah C., additional, O'Connor, Desmond, additional, Marshall, George, additional, Rycroft, W., additional, and MacLeod, Angus M., additional

Published
2004
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12. Identification of a Novel, Selective GABAAα5 Receptor Inverse Agonist Which Enhances Cognition

Author

Chambers, Mark S., primary, Atack, John R., additional, Broughton, Howard B., additional, Collinson, Neil, additional, Cook, Susan, additional, Dawson, Gerard R., additional, Hobbs, Sarah C., additional, Marshall, George, additional, Maubach, Karen A., additional, Pillai, Goplan V., additional, Reeve, Austin J., additional, and MacLeod, Angus M., additional

Published
2003
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13. 6,7-Dihydro-2-benzothiophen-4(5H)-ones: A Novel Class of GABA-A α5 Receptor Inverse Agonists

Author

Chambers, Mark S., primary, Atack, John R., additional, Bromidge, Frances A., additional, Broughton, Howard B., additional, Cook, Susan, additional, Dawson, Gerard R., additional, Hobbs, Sarah C., additional, Maubach, Karen A., additional, Reeve, Austin J., additional, Seabrook, Guy R., additional, Wafford, Keith, additional, and MacLeod, Angus M., additional

Published
2002
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14. Discovery of Highly Potent,Selective, and Brain-PenetrantAminopyrazole Leucine-Rich Repeat Kinase 2 (LRRK2) Small MoleculeInhibitors.

Author

Estrada, Anthony A., Chan, Bryan K., Baker-Glenn, Charles, Beresford, Alan, Burdick, Daniel J., Chambers, Mark, Chen, Huifen, Dominguez, Sara L., Dotson, Jennafer, Drummond, Jason, Flagella, Michael, Fuji, Reina, Gill, Andrew, Halladay, Jason, Harris, Seth F., Heffron, Timothy P., Kleinheinz, Tracy, Lee, Donna W., Pichon, Claire E. Le, and Liu, Xingrong

Published
2014
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15. 3-(Piperazinylpropyl)indoles: Selective, Orally Bioavailable h5-HT1DReceptor Agonists as Potential Antimigraine Agents

Author

Chambers, Mark S., primary, Street, Leslie J., additional, Goodacre, Simon, additional, Hobbs, Sarah C., additional, Hunt, Peter, additional, Jelley, Richard A., additional, Matassa, Victor G., additional, Reeve, Austin J., additional, Sternfeld, Francine, additional, Beer, Margaret S., additional, Stanton, Josephine A., additional, Rathbone, Denise, additional, Watt, Alan P., additional, and MacLeod, Angus M., additional

Published
1999
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17. Discovery of Highly Potent,Selective, and Brain-Penetrable Leucine-Rich Repeat Kinase 2 (LRRK2)Small Molecule Inhibitors.

Author

Estrada, Anthony A., Liu, Xingrong, Baker-Glenn, Charles, Beresford, Alan, Burdick, Daniel J., Chambers, Mark, Chan, Bryan K., Chen, Huifen, Ding, Xiao, DiPasquale, AntonioG., Dominguez, Sara L., Dotson, Jennafer, Drummond, Jason, Flagella, Michael, Flynn, Sean, Fuji, Reina, Gill, Andrew, Gunzner-Toste, Janet, Harris, Seth F., and Heffron, Timothy P.

Published
2012
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20. An orally bioavailable, functionally selective inverse agonist at the benzodiazepine site of GABAA alpha5 receptors with cognition enhancing properties.

Author

Chambers MS, Atack JR, Carling RW, Collinson N, Cook SM, Dawson GR, Ferris P, Hobbs SC, O'connor D, Marshall G, Rycroft W, and Macleod AM

Subjects
Administration, Oral, Animals, Binding Sites, Biological Availability, Dogs, Isoxazoles adverse effects, Isoxazoles pharmacology, Maze Learning drug effects, Mice, Nootropic Agents adverse effects, Nootropic Agents pharmacology, Patch-Clamp Techniques, Protein Subunits, Radioligand Assay, Rats, Receptors, GABA-A metabolism, Triazines adverse effects, Triazines pharmacology, Cognition drug effects, GABA-A Receptor Agonists, Isoxazoles chemical synthesis, Nootropic Agents chemical synthesis, Triazines chemical synthesis
Abstract

(3-tert-Butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine (13) has been identified as a functionally selective, inverse agonist at the benzodiazepine site of GABA(A) alpha5 receptors. 13 is orally bioavailable, readily penetrates the CNS, and enhances performance in animal models of cognition. It does not exhibit the convulsant, proconvulsant, or anxiogenic activity associated with nonselective GABA(A) inverse agonists.

Published
2004
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21. Identification of a novel, selective GABA(A) alpha5 receptor inverse agonist which enhances cognition.

Author

Chambers MS, Atack JR, Broughton HB, Collinson N, Cook S, Dawson GR, Hobbs SC, Marshall G, Maubach KA, Pillai GV, Reeve AJ, and MacLeod AM

Subjects
Animals, Brain metabolism, Cell Line, Female, GABA Agonists adverse effects, GABA Agonists pharmacology, Hippocampus physiology, Humans, In Vitro Techniques, Ligands, Male, Maze Learning drug effects, Memory drug effects, Mice, Nootropic Agents adverse effects, Nootropic Agents pharmacology, Oocytes drug effects, Oocytes physiology, Patch-Clamp Techniques, Protein Subunits, Radioligand Assay, Rats, Seizures chemically induced, Structure-Activity Relationship, Thiazoles adverse effects, Thiazoles pharmacology, Thiophenes adverse effects, Thiophenes pharmacology, Xenopus laevis, Cognition drug effects, GABA Agonists chemical synthesis, Nootropic Agents chemical synthesis, Receptors, GABA-A drug effects, Thiazoles chemical synthesis, Thiophenes chemical synthesis
Abstract

In pursuit of a GABA(A) alpha5-subtype-selective inverse agonist to enhance cognition, a series of 6,7-dihydro-2-benzothiophen-4(5H)-ones has been identified as a novel class of GABA(A) receptor ligands. These thiophenes have higher binding affinity for the GABA(A) alpha5 receptor subtype compared to the GABA(A) alpha1, alpha2, and alpha3 subtypes, and several analogues exhibit high GABA(A) alpha5 receptor inverse agonism. 6,6-Dimethyl-3-(2-hydroxyethyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one (43) has been identified as a full inverse agonist at the GABA(A) alpha5 receptor and is functionally selective over the other major GABA(A) receptor subtypes. 43 readily penetrates into the CNS to give selective occupancy of GABA(A) alpha5 receptors. In addition, 43 enhances cognitive performance in rats in the delayed 'matching-to-place' Morris water maze test-a hippocampal-dependent memory task-without the convulsant or proconvulsant activity associated with nonselective, GABA(A) receptor inverse agonists.

Published
2003
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22. 6,7-Dihydro-2-benzothiophen-4(5H)-ones: a novel class of GABA-A alpha5 receptor inverse agonists.

Author

Chambers MS, Atack JR, Bromidge FA, Broughton HB, Cook S, Dawson GR, Hobbs SC, Maubach KA, Reeve AJ, Seabrook GR, Wafford K, and MacLeod AM

Subjects
Animals, Cells, Cultured, Cognition, Humans, Ketones pharmacology, Mice, Thiazoles chemical synthesis, Thiazoles pharmacology, Thiophenes pharmacology, Xenopus laevis, GABA-A Receptor Agonists, Ketones chemical synthesis, Thiophenes chemical synthesis
Abstract

Nonselective inverse agonists at the benzodiazepine binding site on the GABA-A chloride ion channel enhance cognitive performance in animals but cannot be used in the treatment of cognitive disorders because of anxiogenic and convulsant side effects. We have identified a novel series of GABA-A alpha5 receptor ligands during our search for alpha5 receptor inverse agonists as potential cognition enhancers. In particular, 6,6-dimethyl-3-(2-hydroxyethyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one (26) has been identified as a functionally selective GABA-A alpha5 inverse agonist.

Published
2002
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