7 results on '"Bazaga, Santiago Ferrer"'
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2. A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance
- Author
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O'Neill, Paul M., Amewu, Richard K., Charman, Susan A., Sabbani, Sunil, Gnädig, Nina F., Straimer, Judith, Fidock, David A., Shore, Emma R., Roberts, Natalie L., Wong, Michael H.-L., Hong, W. David, Pidathala, Chandrakala, Riley, Chris, Murphy, Ben, Aljayyoussi, Ghaith, Gamo, Francisco Javier, Sanz, Laura, Rodrigues, Janneth, Cortes, Carolina Gonzalez, Herreros, Esperanza, Angulo-Barturén, Iñigo, Jiménez-Díaz, María Belén, Bazaga, Santiago Ferrer, Martínez-Martínez, María Santos, Campo, Brice, Sharma, Raman, Ryan, Eileen, Shackleford, David M., Campbell, Simon, Smith, Dennis A., Wirjanata, Grennady, Noviyanti, Rintis, Price, Ric N., Marfurt, Jutta, Palmer, Michael J., Copple, Ian M., Mercer, Amy E., Ruecker, Andrea, Delves, Michael J., Sinden, Robert E., Siegl, Peter, Davies, Jill, Rochford, Rosemary, Kocken, Clemens H. M., Zeeman, Anne-Marie, Nixon, Gemma L., Biagini, Giancarlo A., and Ward, Stephen A.
- Subjects
Male ,Erythrocytes ,Science ,Plasmodium falciparum ,Drug Resistance ,Protozoan Proteins ,Mice, SCID ,qv_38 ,wc_765 ,Article ,Rats, Sprague-Dawley ,Antimalarials ,Mice ,Dogs ,Mice, Inbred NOD ,qx_600 ,parasitic diseases ,qv_256 ,Animals ,Humans ,Transgenes ,Dose-Response Relationship, Drug ,Artemisinins ,wc_750 ,Rats ,qx_20 ,Mutation ,Female ,Plasmodium vivax ,Tetraoxanes ,Half-Life - Abstract
K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives., Artemisinin-resistant Plasmodium is an increasing problem. Here, using a medicinal chemistry programme, the authors identify a tetraoxane-based drug candidate that shows no cross-resistance with an artemisinin-resistant strain (PfK13-C580Y) and is efficient in Plasmodium mouse models.
- Published
- 2017
3. A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance
- Author
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O’Neill, Paul M., primary, Amewu, Richard K., additional, Charman, Susan A., additional, Sabbani, Sunil, additional, Gnädig, Nina F., additional, Straimer, Judith, additional, Fidock, David A., additional, Shore, Emma R., additional, Roberts, Natalie L., additional, Wong, Michael H.-L., additional, Hong, W. David, additional, Pidathala, Chandrakala, additional, Riley, Chris, additional, Murphy, Ben, additional, Aljayyoussi, Ghaith, additional, Gamo, Francisco Javier, additional, Sanz, Laura, additional, Rodrigues, Janneth, additional, Cortes, Carolina Gonzalez, additional, Herreros, Esperanza, additional, Angulo-Barturén, Iñigo, additional, Jiménez-Díaz, María Belén, additional, Bazaga, Santiago Ferrer, additional, Martínez-Martínez, María Santos, additional, Campo, Brice, additional, Sharma, Raman, additional, Ryan, Eileen, additional, Shackleford, David M., additional, Campbell, Simon, additional, Smith, Dennis A., additional, Wirjanata, Grennady, additional, Noviyanti, Rintis, additional, Price, Ric N., additional, Marfurt, Jutta, additional, Palmer, Michael J., additional, Copple, Ian M., additional, Mercer, Amy E., additional, Ruecker, Andrea, additional, Delves, Michael J., additional, Sinden, Robert E., additional, Siegl, Peter, additional, Davies, Jill, additional, Rochford, Rosemary, additional, Kocken, Clemens H. M., additional, Zeeman, Anne-Marie, additional, Nixon, Gemma L., additional, Biagini, Giancarlo A., additional, and Ward, Stephen A., additional
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- 2017
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4. A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria
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Phillips, Margaret A., primary, White, Karen L., additional, Kokkonda, Sreekanth, additional, Deng, Xiaoyi, additional, White, John, additional, El Mazouni, Farah, additional, Marsh, Kennan, additional, Tomchick, Diana R., additional, Manjalanagara, Krishne, additional, Rudra, Kakali Rani, additional, Wirjanata, Grennady, additional, Noviyanti, Rintis, additional, Price, Ric N., additional, Marfurt, Jutta, additional, Shackleford, David M., additional, Chiu, Francis C. K., additional, Campbell, Michael, additional, Jimenez-Diaz, Maria Belen, additional, Bazaga, Santiago Ferrer, additional, Angulo-Barturen, Iñigo, additional, Martinez, Maria Santos, additional, Lafuente-Monasterio, Maria, additional, Kaminsky, Werner, additional, Silue, Kigbafori, additional, Zeeman, Anne-Marie, additional, Kocken, Clemens, additional, Leroy, Didier, additional, Blasco, Benjamin, additional, Rossignol, Emilie, additional, Rueckle, Thomas, additional, Matthews, Dave, additional, Burrows, Jeremy N., additional, Waterson, David, additional, Palmer, Michael J., additional, Rathod, Pradipsinh K., additional, and Charman, Susan A., additional
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- 2016
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5. Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity
- Author
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Kokkonda, Sreekanth, primary, Deng, Xiaoyi, additional, White, Karen L., additional, Coteron, Jose M., additional, Marco, Maria, additional, de las Heras, Laura, additional, White, John, additional, El Mazouni, Farah, additional, Tomchick, Diana R., additional, Manjalanagara, Krishne, additional, Rudra, Kakali Rani, additional, Chen, Gong, additional, Morizzi, Julia, additional, Ryan, Eileen, additional, Kaminsky, Werner, additional, Leroy, Didier, additional, Martínez-Martínez, María Santos, additional, Jimenez-Diaz, Maria Belen, additional, Bazaga, Santiago Ferrer, additional, Angulo-Barturen, Iñigo, additional, Waterson, David, additional, Burrows, Jeremy N., additional, Matthews, Dave, additional, Charman, Susan A., additional, Phillips, Margaret A., additional, and Rathod, Pradipsinh K., additional
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- 2016
- Full Text
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6. A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria
- Author
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Phillips, Margaret A., primary, Lotharius, Julie, additional, Marsh, Kennan, additional, White, John, additional, Dayan, Anthony, additional, White, Karen L., additional, Njoroge, Jacqueline W., additional, El Mazouni, Farah, additional, Lao, Yanbin, additional, Kokkonda, Sreekanth, additional, Tomchick, Diana R., additional, Deng, Xiaoyi, additional, Laird, Trevor, additional, Bhatia, Sangeeta N., additional, March, Sandra, additional, Ng, Caroline L., additional, Fidock, David A., additional, Wittlin, Sergio, additional, Lafuente-Monasterio, Maria, additional, Benito, Francisco Javier Gamo, additional, Alonso, Laura Maria Sanz, additional, Martinez, Maria Santos, additional, Jimenez-Diaz, Maria Belen, additional, Bazaga, Santiago Ferrer, additional, Angulo-Barturen, Iñigo, additional, Haselden, John N., additional, Louttit, James, additional, Cui, Yi, additional, Sridhar, Arun, additional, Zeeman, Anna-Marie, additional, Kocken, Clemens, additional, Sauerwein, Robert, additional, Dechering, Koen, additional, Avery, Vicky M., additional, Duffy, Sandra, additional, Delves, Michael, additional, Sinden, Robert, additional, Ruecker, Andrea, additional, Wickham, Kristina S., additional, Rochford, Rosemary, additional, Gahagen, Janet, additional, Iyer, Lalitha, additional, Riccio, Ed, additional, Mirsalis, Jon, additional, Bathhurst, Ian, additional, Rueckle, Thomas, additional, Ding, Xavier, additional, Campo, Brice, additional, Leroy, Didier, additional, Rogers, M. John, additional, Rathod, Pradipsinh K., additional, Burrows, Jeremy N., additional, and Charman, Susan A., additional
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- 2015
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7. Model-based effect evaluation of a novel Mmpl3 inhibitor in C3HeB/FeJ compared to BALB/c mouse models and translation to humans
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Ayoun Alsoud, Rami, Keutzer, Lina, Hölscher, Christoph, Redinger, Natalja, Hölscher, Alexandra, Schaible, Ulrich, Bazaga, Santiago Ferrer, Fotouhi, Nader, Serbina, Natalya, Simonsson, Ulrika S. H., Ayoun Alsoud, Rami, Keutzer, Lina, Hölscher, Christoph, Redinger, Natalja, Hölscher, Alexandra, Schaible, Ulrich, Bazaga, Santiago Ferrer, Fotouhi, Nader, Serbina, Natalya, and Simonsson, Ulrika S. H.
- Abstract
Background and Purpose: During tuberculosis drug development, the design of early clinical studies is informed by preclinical animal models. The aim of this work was to describe the exposure-response relationship of a novel inhibitor of mycobacterial MmpL3, prodrug MPL-447, in C3HeB/FeJ mice with non-necrotic or necrotic lesions, and to compare to chronic BALB/c mice information. Experimental Approach: C3HeB/FeJ mice were randomised to placebo and three treatment groups (25, 50 or 100 mg/kg MPL-447). Colony forming unit (CFU) were obtained until week 8 post-treatment. Semi-mechanistic modelling was used to describe growth and killing in relation to exposure. Early bactericidal activity after 14 days (EBA0-14) in humans was predicted using the final model, translational factors and allometric scaling of pharmacokinetics to humans and compared to chronic BALB/c. Key Results: The final model showed 1100% growth and 42% killing of the fast-multiplying bacteria in C3HeB/FeJ mice with necrotic lesions compared to those with non-necrotic lesions. Simulations revealed similar log10CFU reduction on day 14 in C3HeB/FeJ mice with non-necrotic lesions as in chronic BALB/c mice in response to treatment, but 1.7-fold lower reduction in C3HeB/FeJ mice with necrotic lesions. Similar human EBA0-14 was predicted irrespective of the mouse model used. Conclusion and Implications: The difference in killing of fast-multiplying bacteria in C3HeB/FeJ mice with necrotic lesions compared to C3HeB/FeJ mice without or chronic BALB/C mice was not translated to human early clinical predictions, most likely due to low abundance of these bacteria in humans.
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