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Your search keyword '"Harrison, Justin R."' showing total 8 results
Start Over Author "Harrison, Justin R." Journal journal of medicinal chemistry
8 results on '"Harrison, Justin R."'

1. Repositioning of a Diaminothiazole Series Confirmed to Target the Cyclin-Dependent Kinase CRK12 for Use in the Treatment of African Animal Trypanosomiasis

Author

Smith, Alasdair, primary, Wall, Richard J., additional, Patterson, Stephen, additional, Rowan, Tim, additional, Rico Vidal, Eva, additional, Stojanovski, Laste, additional, Huggett, Margaret, additional, Hampton, Shahienaz E., additional, Thomas, Michael G., additional, Corpas Lopez, Victoriano, additional, Gillingwater, Kirsten, additional, Duke, Jeff, additional, Napier, Grant, additional, Peter, Rose, additional, Vitouley, Hervé S., additional, Harrison, Justin R., additional, Milne, Rachel, additional, Jeacock, Laura, additional, Baker, Nicola, additional, Davis, Susan H., additional, Simeons, Frederick, additional, Riley, Jennifer, additional, Horn, David, additional, Brun, Reto, additional, Zuccotto, Fabio, additional, Witty, Michael J, additional, Wyllie, Susan, additional, Read, Kevin D., additional, and Gilbert, Ian H., additional

Published
2022
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2. Discovery and Optimization of a Compound Series Active against Trypanosoma cruzi, the Causative Agent of Chagas Disease

Author

Harrison, Justin R., primary, Sarkar, Sandipan, additional, Hampton, Shahienaz, additional, Riley, Jennifer, additional, Stojanovski, Laste, additional, Sahlberg, Christer, additional, Appelqvist, Pia, additional, Erath, Jessey, additional, Mathan, Vinodhini, additional, Rodriguez, Ana, additional, Kaiser, Marcel, additional, Pacanowska, Dolores Gonzalez, additional, Read, Kevin D., additional, Johansson, Nils Gunnar, additional, and Gilbert, Ian H., additional

Published
2020
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3. Lead Optimization of a Pyrazole Sulfonamide Series of Trypanosoma bruceiN-Myristoyltransferase Inhibitors: Identification and Evaluation of CNS Penetrant Compounds as Potential Treatments for Stage 2 Human African Trypanosomiasis

Author

Brand, Stephen, Norcross, Neil R., Thompson, Stephen, Harrison, Justin R., Smith, Victoria C., Robinson, David A., Torrie, Leah S., McElroy, Stuart P., Hallyburton, Irene, Norval, Suzanne, Scullion, Paul, Stojanovski, Laste, Simeons, Frederick R. C., van Aalten, Daan, Frearson, Julie A., Brenk, Ruth, Fairlamb, Alan H., Ferguson, Michael A. J., Wyatt, Paul G., Gilbert, Ian H., and Read, Kevin D.

Subjects
Central Nervous System, Sulfonamides, Trypanosoma brucei brucei, Aminopyridines, Trypanocidal Agents, Article, Inhibitory Concentration 50, Mice, Structure-Activity Relationship, Trypanosomiasis, African, Blood-Brain Barrier, Animals, Humans, Pyrazoles, Female, Acyltransferases
Abstract

Trypanosoma brucei N-myristoyltransferase (TbNMT) is an attractive therapeutic target for the treatment of human African trypanosomiasis (HAT). From previous studies, we identified pyrazole sulfonamide, DDD85646 (1), a potent inhibitor of TbNMT. Although this compound represents an excellent lead, poor central nervous system (CNS) exposure restricts its use to the hemolymphatic form (stage 1) of the disease. With a clear clinical need for new drug treatments for HAT that address both the hemolymphatic and CNS stages of the disease, a chemistry campaign was initiated to address the shortfalls of this series. This paper describes modifications to the pyrazole sulfonamides which markedly improved blood-brain barrier permeability, achieved by reducing polar surface area and capping the sulfonamide. Moreover, replacing the core aromatic with a flexible linker significantly improved selectivity. This led to the discovery of DDD100097 (40) which demonstrated partial efficacy in a stage 2 (CNS) mouse model of HAT.

Published
2014

4. A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors

Author

Harrison, Justin R., primary, Brand, Stephen, additional, Smith, Victoria, additional, Robinson, David A., additional, Thompson, Stephen, additional, Smith, Alasdair, additional, Davies, Kenneth, additional, Mok, Ngai, additional, Torrie, Leah S., additional, Collie, Iain, additional, Hallyburton, Irene, additional, Norval, Suzanne, additional, Simeons, Frederick R. C., additional, Stojanovski, Laste, additional, Frearson, Julie A., additional, Brenk, Ruth, additional, Wyatt, Paul G., additional, Gilbert, Ian H., additional, and Read, Kevin D., additional

Published
2018
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5. Lead Optimization of a Pyrazole Sulfonamide Series of Trypanosoma brucei N-Myristoyltransferase Inhibitors: Identification and Evaluation of CNS Penetrant Compounds as Potential Treatments for Stage 2 Human African Trypanosomiasis

Author

Brand, Stephen, primary, Norcross, Neil R., additional, Thompson, Stephen, additional, Harrison, Justin R., additional, Smith, Victoria C., additional, Robinson, David A., additional, Torrie, Leah S., additional, McElroy, Stuart P., additional, Hallyburton, Irene, additional, Norval, Suzanne, additional, Scullion, Paul, additional, Stojanovski, Laste, additional, Simeons, Frederick R. C., additional, van Aalten, Daan, additional, Frearson, Julie A., additional, Brenk, Ruth, additional, Fairlamb, Alan H., additional, Ferguson, Michael A. J., additional, Wyatt, Paul G., additional, Gilbert, Ian H., additional, and Read, Kevin D., additional

Published
2014
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6. Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors

Author

Brand, Stephen, primary, Cleghorn, Laura A. T., additional, McElroy, Stuart P., additional, Robinson, David A., additional, Smith, Victoria C., additional, Hallyburton, Irene, additional, Harrison, Justin R., additional, Norcross, Neil R., additional, Spinks, Daniel, additional, Bayliss, Tracy, additional, Norval, Suzanne, additional, Stojanovski, Laste, additional, Torrie, Leah S., additional, Frearson, Julie A., additional, Brenk, Ruth, additional, Fairlamb, Alan H., additional, Ferguson, Michael A. J., additional, Read, Kevin D., additional, Wyatt, Paul G., additional, and Gilbert, Ian H., additional

Published
2011
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7. Lead Optimization of a PyrazoleSulfonamide Seriesof Trypanosoma bruceiN-Myristoyltransferase Inhibitors: Identification and Evaluationof CNS Penetrant Compounds as Potential Treatments for Stage 2 HumanAfrican Trypanosomiasis.

Author

Brand, Stephen, Norcross, Neil R., Thompson, Stephen, Harrison, Justin R., Smith, Victoria C., Robinson, David A., Torrie, Leah S., McElroy, Stuart P., Hallyburton, Irene, Norval, Suzanne, Scullion, Paul, Stojanovski, Laste, Simeons, Frederick R. C., van Aalten, Daan, Frearson, Julie A., Brenk, Ruth, Fairlamb, Alan H., Ferguson, Michael A. J., Wyatt, Paul G., and Gilbert, Ian H.

Published
2014
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8. Discovery of a novel class of orally active trypanocidal N-myristoyltransferase inhibitors.

Author

Brand S, Cleghorn LA, McElroy SP, Robinson DA, Smith VC, Hallyburton I, Harrison JR, Norcross NR, Spinks D, Bayliss T, Norval S, Stojanovski L, Torrie LS, Frearson JA, Brenk R, Fairlamb AH, Ferguson MA, Read KD, Wyatt PG, and Gilbert IH

Subjects
Administration, Oral, Aminopyridines pharmacokinetics, Aminopyridines pharmacology, Animals, Cell Line, Cell Survival drug effects, Crystallography, X-Ray, Databases, Factual, Humans, Models, Molecular, Molecular Conformation, Parasitic Sensitivity Tests, Structure-Activity Relationship, Sulfonamides pharmacokinetics, Sulfonamides pharmacology, Trypanocidal Agents pharmacokinetics, Trypanocidal Agents pharmacology, Trypanosoma brucei brucei drug effects, Trypanosomiasis, African drug therapy, Acyltransferases antagonists & inhibitors, Aminopyridines chemical synthesis, Sulfonamides chemical synthesis, Trypanocidal Agents chemical synthesis
Abstract

N-Myristoyltransferase (NMT) represents a promising drug target for human African trypanosomiasis (HAT), which is caused by the parasitic protozoa Trypanosoma brucei. We report the optimization of a high throughput screening hit (1) to give a lead molecule DDD85646 (63), which has potent activity against the enzyme (IC(50) = 2 nM) and T. brucei (EC(50) = 2 nM) in culture. The compound has good oral pharmacokinetics and cures rodent models of peripheral HAT infection. This compound provides an excellent tool for validation of T. brucei NMT as a drug target for HAT as well as a valuable lead for further optimization.

Published
2012
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