Spiroindolones, a potent compound class for the treatment of malaria

Science

Volumn 329, Issue 5996, 2010, Pages 1175-1180

  Rottmann, Matthias ^a,b   McNamara, Case ^c   Yeung, Bryan K S ^d   Lee, Marcus C S ^e   Zou, Bin ^d   Russell, Bruce ^f,g   Seitz, Patrick ^a,b   Plouffe, David M ^c   Dharia, Neekesh V ^h   Tan, Jocelyn ^d   Cohen, Steven B ^c   Spencer, Kathryn R ^h   González Páez, Gonzalo E ^h   Lakshminarayana, Suresh B ^d   Goh, Anne ^d   Suwanarusk, Rossarin ^f   Jegla, Timothy ⁱ   Schmitt, Esther K ^j   Beck, Hans Peter ^a,b   Brun, Reto ^a,b   Nosten, Francois ^k,l,m   Renia, Laurent ^f   Dartois, Veronique ^d   Keller, Thomas H ^d   Fidock, David A ^e   Winzeler, Elizabeth A ^c,h   Diagana, Thierry T ^d   more..

^a SWISS TROPICAL AND PUBLIC HEALTH INSTITUTE   (Switzerland)

^b UNIVERSITY OF BASEL   (Switzerland)

^c GENOMICS INSTITUTE OF THE NOVARTIS RESEARCH FOUNDATION   (United States)

^d NOVARTIS INSTITUTE FOR TROPICAL DISEASES   (Singapore)

^e NewYork Presbyterian Hospital   (United States)

^f AGENCY FOR SCIENCE   (Singapore)

^g NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

^h SCRIPPS RESEARCH INSTITUTE   (United States)

ⁱ PENNSYLVANIA STATE UNIVERSITY   (United States)

^j NOVARTIS PHARMA AG   (Switzerland)

^k SHOKLO MALARIA RESEARCH UNIT   (Thailand)

^l MAHIDOL UNIVERSITY   (Thailand)

^m UNIVERSITY OF OXFORD   (United Kingdom)

more..

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE TRIPHOSPHATASE; ANTIMALARIAL AGENT; ARTEMETHER; ARTESUNATE; CHLOROQUINE; MEFLOQUINE; NITD 609; P TYPE CATION TRANSPORTER ATPASE4; SPIROINDOLONE DERIVATIVE; UNCLASSIFIED DRUG; INDOLE DERIVATIVE; MUTANT PROTEIN; PROTEIN SYNTHESIS INHIBITOR; PROTOZOAL PROTEIN; SPIRO COMPOUND;

ANTIMALARIAL AGENT; BLOOD; CATION; DRUG; ENZYME ACTIVITY; EXPERIMENTAL STUDY; MALARIA; PROTEIN; RODENT; TOLERANCE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIMALARIAL ACTIVITY; AREA UNDER THE CURVE; ARTICLE; CELL PROLIFERATION; CONCENTRATION RESPONSE; CONTROLLED STUDY; CYTOTOXICITY; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG HALF LIFE; DRUG METABOLISM; DRUG SAFETY; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TOLERABILITY; GENE MUTATION; MALARIA; MALE; MOUSE; NONHUMAN; PLASMODIUM FALCIPARUM; PLASMODIUM VIVAX; PRIORITY JOURNAL; PROTEIN SYNTHESIS; RAT; SCREENING; SURVIVAL RATE; ANIMAL; ANTAGONISTS AND INHIBITORS; BIOSYNTHESIS; CELL LINE; CHEMICAL STRUCTURE; CHEMISTRY; DRUG DEVELOPMENT; DRUG EFFECTS; DRUG RESISTANCE; DRUG SENSITIVITY; ERYTHROCYTE; FEMALE; GENE; GENETICS; GROWTH, DEVELOPMENT AND AGING; HUMAN; METABOLISM; MUTATION; PARASITOLOGY; PLASMODIUM BERGHEI; WISTAR RAT;

ADENOSINE TRIPHOSPHATASES; ANIMALS; ANTIMALARIALS; CELL LINE; DRUG DISCOVERY; DRUG RESISTANCE; ERYTHROCYTES; FEMALE; GENES, PROTOZOAN; HUMANS; INDOLES; MALARIA; MALE; MICE; MODELS, MOLECULAR; MUTANT PROTEINS; MUTATION; PARASITIC SENSITIVITY TESTS; PLASMODIUM BERGHEI; PLASMODIUM FALCIPARUM; PLASMODIUM VIVAX; PROTEIN SYNTHESIS INHIBITORS; PROTOZOAN PROTEINS; RATS; RATS, WISTAR; SPIRO COMPOUNDS;

EID: 77956280420     PISSN: 00368075     EISSN: 10959203     Source Type: Journal    
DOI: 10.1126/science.1193225     Document Type: Article

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44. We thank A. Matter, M. Tanner, and P. Herrling for their foresight and support in establishing a malaria drug discovery program in the context of a public-private partnership. We thank T. A. Smith (SwissTPH) for the statistical analysis of the stage and rate of action studies. We thank S. Rao (Novartis Institute for Tropical Diseases) and M. Traebert (Novartis-preclinical safety), respectively, for the cytotoxicity and hERG inhibition data. We also thank M. Weaver (Novartis-preclinical safety) for the interpretation of the preclinical toxicology data. The team acknowledges P. Schultz, who had the vision to see the potential of the drug resistance experiments in the exploratory phase. In addition, we are grateful to R. T. Eastman for providing guidance to establish the in vitro drug-selection protocol and for providing the cloned Dd2 parasites. Finally, the scientific expertise provided by S. E. R. Bopp and S. K. Sharma and their helpful discussions throughout this project are greatly appreciated. Funding for the PfATP4 transfectants was provided to the Fidock laboratory in part by the Medicines for Malaria Venture (MMV08/0015; PI D. Fidock). The Shoklo Malaria Research Unit is sponsored by the Wellcome Trust of Great Britain, as part of the Oxford Tropical Medicine Research Programme of Wellcome Trust-Mahidol University. Laurent Renia's laboratory is supported by a core grant from the Singapore Immunology Network, A*STAR. This work was supported by a grant from the Medicines for Malaria Venture and a translational research grant (WT078285) from the Wellcome Trust to the Novartis Institute for Tropical Diseases, the Genomics Institute of the Novartis Research Foundation and the Swiss Tropical Institute, and by grants to E.A.W. from the W. M. Keck Foundation and the NIH (R01AI059472). NITD609 is described in the Novartis patent application WO2009/132921. All requests for spiroindolones or related compounds are subject to a Material Transfer Agreement. T.H.K. and E.A.W. own shares in Novartis (Switzerland).