Journal of Medicinal Chemistry
ARTICLE
Compound 10 is currently undergoing iv and oral pharmacoki-
netic analyses and brain/plasma tissue binding studies which will
be disseminated in due course.
comparing sulfadoxine-pyrimethamine with mefloquine. J. Infect. Dis.
2009, 200, 991–1001.
(3) McGready, R. Intermittent preventive treatment of infants with
mefloquine reduces risk of clinical malaria in areas of moderate malaria
transmission and high resistance to sulphadoxine-pyrimethamine, but
safety and tolerability issues need consideration. Evidence-Based Med.
2010, 15, 71–72.
(4) Milner, E.; McCalmont, W.; Bhonsle, J.; Caridha, D.; Cobar, J.;
Gardner, S.; Gerena, L.; Goodine, D.; Lanteri, C.; Melendez, V.; Roncal,
N.; Sousa, J.; Wipf, P.; Dow, G. Anti-malarial activity of a non-piperidine
library of next-generation quinoline methanols. Malar. J. 2010, 9, 51.
(5) Milner, E.; McCalmont, W.; Bhonsle, J.; Caridha, D.; Carroll, D.;
Gardner, S.; Gerena, L.; Gettayacamin, M.; Lanteri, C.; Luong, T.;
Melendez, V.; Moon, J.; Roncal, N.; Sousa, J.; Tangteung, A.; Wipf, P.;
Dow, G. StructureÀactivity relationships amongst 4-position quinoline
methanol antimalarials that inhibit the growth of drug sensitive and
resistant strains of Plasmodium falciparum. Bioorg. Med. Chem. Lett. 2010,
20, 1347–1351.
’ ASSOCIATED CONTENT
S
Supporting Information. Biological protocols, synthetic
b
methods, and analytical data for all compounds described in this
study. This material is available free of charge via the Internet at
’ AUTHOR INFORMATION
Corresponding Author
*Phone: 301-319-9461. Fax: 301-319-9449. E-mail: erin.milner@
amedd.army.mil.
(6) Dow, G.; Milner, E.; Bathurst, I; Bhonsle, J.; Caridha, D.;
Gardner, S.; Gerena, L.; Kozar, M.; Lanteri, C.; Mannila, A.;
McCalmont, W.; Melendez, V.; Moon, J.; Read, K.; Norval, S.; Roncal,
N.; Shackleford, D.; Sousa, J.; Stouten, J.; White, K.; Zeng, Q.; Charman,
S. Central nervous system (CNS) exposure of next generation quinoline
methanols is reduced relative to mefloquine after intravenous (IV)
dosing in mice. Malar. J. 2011, 10, 150.
(7) (a) Wipf, P.; Mo, T.; Geib, S.; Caridha, D.; Dow, G.; Gerena, L.;
Roncal, N.; Milner, E. Synthesis and biological evaluation of the first
pentafluorosulfanyl analogs of mefloquine. Org. Biomol. Chem. 2009,
7, 4163–4165. (b) Mo, T.; Milner, E.; Dow, G.; Wipf, P. Synthesis of
8-pentafluorosulfanyl analog of the antimalarial agent mefloquine.
Tetrahedron Lett. 2010, 51, 5137–5140.
(8) Initially (+)- and (À)-enantiomers of epoxide 3 were obtained
via supercritical fluid chromatographic separation performed by Regis
tion for chromatogram). Once a lead candidate was declared, the bulk
synthesis of the corresponding (+) enantiomer of epoxide 3 was out-
sourced to Bioblocks (http://www.bioblocks.com).
(9) The Walter Reed (WR) code numbers in this manuscript are
included in a provisional patent and recent invention disclosure:
(a) Dow, G.; Milner, E.; McCalmont, W. Next Generation Quinoline
Methanols. PCT US0955796. September 2, 2009. (b) Milner, E. E.;
Dow, G. S. 4-Position Diamine Quinoline Methanols as Intermittent
Preventative Treatment (IPT) against Plasmodium falciparum. Inven-
tion Disclosure Filed January 28, 2011.
(10) Milner, E.; Sousa, J.; Pybus, B.; Melendez, V.; Gardner, S.;
Grauer, K.; Moon, J.; Carroll, D.; Auschwitz, J.; Gettayacamin, M.; Lee, P.;
Leed, S.; Norval, S.; Tungtaeng, A.; Zeng, Q.; Kozar, M.; D Read, K.; Li, Q.;
Dow, G. Characterization of in vivo metabolites of WR319691, a novel
compound with activity against Plasmodium falciparum. Eur. J. Drug Metab.
Pharmacokinet. [Online early access]. Published Online: Jul 13, 2011.
(11) United States Food and Drug Administration, Center for Drug
Evaluation and Research. Development of New Stereoisomeric Drugs;
United States Department of Health and Human Services: Washington,
toryInformation/Guidances/.
’ ACKNOWLEDGMENT
This manuscript was reviewed by the Walter Reed Army
Institute of Research and the U.S. Army Medical Research and
Materiel Command, and there is no objection to its publication
or dissemination. The opinions expressed herein are those of the
authors and do not necessarily reflect the views or opinions of the
Department of the Army and the Department of Defense. All
animal experiments were conducted in compliance with the
Animal Welfare Act and other federal statutes and regulations
relating to animals and experiments involving animals and adhere to
the principles stated in the Guide for the Care and Use of Laboratory
Animals (National Academy Press, 1996). The MDCK permeabil-
ity assays were performed under contract by Absorption Systems
(Exton, PA). The authors thank Steven Geib of the University of
Pittsburgh for X-ray analysis. We gratefully acknowledge substantial
financial support from Medicines for Malaria Venture, Military
Infectious Diseases Research Program (MIDRP), and the United
States Department of Defense.
’ DEDICATION
†The authors dedicate this manuscript to the memory of Dr. Ian
Bathurst, who served the malaria drug development community
with honor and integrity.
’ ABBREVIATIONS USED
CNS, central nervous system; IPTx, intermittent preventative
treatment, involving periodic administration of a full treatment
level dose of an antimalarial drug to infants (IPTi), to pregnant
women (IPTp), or to travelers (IPTt) in order to prevent malaria
and morbidity; MQ, mefloquine; Pf, Plasmodium falciparum;HBD,
hydrogen bond donor; MDCK, MadinÀDarby canine kidney
(cell line with relatively low transmonolayer permeability); Papp
(Â106 cm/s), apparent permeability; po, per os, which represents
an orally administered dose; iv, intravenous (dose administration)
(12) Hellgren, U.; Angel, V. H.; Bergvist, Y; Arvidsson, A.; Forero-
Gomez, J. S.; Rombo, L. Plasma concentrations of sulfadoxine-pyri-
methamine and of mefloquine during regular long term malaria pro-
phylaxis. Trans. R. Soc. Trop. Med. Hyg. 1990, 84, 46–49.
(13) United States Food and Drug Administration, Center for Drug
Evaluation and Research. Guidance for Industry: Estimating the Maximum
Safe Starting Dose in Initial Clinical Trials for Therapeutics in Healthy
Volunteers; United States Department of Health and Human Services:
plianceRegulatoryInformation/Guidances/
’ REFERENCES
(1) Dow, G. S.; Magill, A. J.; Ohrt, C. Clinical development of new
prophylactic antimalarial drugs after the 5th Amendment to the Declara-
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during pregnancy in Benin: a randomized, open-label equivalence trial
(14) The tables in the article were developed using SAR Vision
software, info@chemapps.com.
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dx.doi.org/10.1021/jm200647u |J. Med. Chem. 2011, 54, 6277–6285