Structure-activity relationships of 4-position diamine quinoline methanols as intermittent preventative treatment (IPT) against plasmodium falciparum

Article abstract of DOI:10.1021/jm200647u

A library of diamine quinoline methanols were designed based on the mefloquine scaffold. The systematic variation of the 4-position amino alcohol side chain led to analogues that maintained potency while reducing accumulation in the central nervous system (CNS). Although the mechanism of action remains elusive, these data indicate that the 4-position side chain is critical for activity and that potency (as measured by IC₉₀) does not correlate with accumulation in the CNS. A new lead compound, (S)-1-(2,8- bis(trifluoromethyl)quinolin-4-yl)-2-(2-(cyclopropylamino)ethylamino)ethanol (WR621308), was identified with single dose efficacy and substantially lower permeability across MDCK cell monolayers than mefloquine. This compound could be appropriate for intermittent preventative treatment (IPTx) indications or other malaria treatments currently approved for mefloquine.

Full text of DOI:10.1021/jm200647u

ARTICLE
pubs.acs.org/jmc
StructureÀActivity Relationships of 4-Position Diamine Quinoline
Methanols as Intermittent Preventative Treatment (IPT) against
Plasmodium falciparum†
Erin Milner,*,‡ Sean Gardner,‡ Jay Moon,‡ Kristina Grauer,‡ Jennifer Auschwitz,‡ Ian Bathurst,^
Diana Caridha,‡ Lucia Gerena,‡ Montip Gettayacamin,§ Jacob Johnson,‡ Michael Kozar,‡ Patricia Lee,‡
Susan Leed,‡ Qigui Li,‡ William McCalmont,‡ Victor Melendez,‡ Norma Roncal,‡ Richard Sciotti,‡
Bryan Smith,‡ Jason Sousa,‡ Anchalee Tungtaeng,§ Peter Wipf,|| and Geoffrey Dow‡
‡Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States
§United States Army Medical Component, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand
Department of Chemistry, University of Pittsburgh, Parkman Avenue, CSC 1301, Pittsburgh, Pennsylvania 15260,
United States
^Medicines for Malaria Venture, International Center Cointrin, Route de Pre-Bois 20, P.O. Box 1826,
CH-1215 Geneva 15, Switzerland
S Supporting Information
b
ABSTRACT: A library of diamine quinoline methanols were
designed based on the mefloquine scaffold. The systematic
variation of the 4-position amino alcohol side chain led to
analogues that maintained potency while reducing accumula-
tion in the central nervous system (CNS). Although the
mechanism of action remains elusive, these data indicate that
the 4-position side chain is critical for activity and that potency
(as measured by IC90) does not correlate with accumulation in
the CNS. A new lead compound, (S)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(2-(cyclopropylamino)ethylamino)ethanol
(WR621308), was identified with single dose efficacy and substantially lower permeability across MDCK cell monolayers than
mefloquine. This compound could be appropriate for intermittent preventative treatment (IPTx) indications or other malaria
treatments currently approved for mefloquine.
’ INTRODUCTION
conceivably serve as a functional replacement for MQ for any
clinical indications, including combination therapy, standby
emergency treatment, intermittent preventative treatment
(IPTx), and prophylaxis. IPTx of malaria involves periodic admin-
istration 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. IPT differs from
standard treatment because individuals are asymptomatic, and it
differs from standard prophylaxis because the administered doses
are higher and not subject to a continuous regimen.1 MQ is
indicated for prophylaxis during pregnancy,2 but the high preva-
lence of central nervous system (CNS) adverse events at treatment
level doses3 will likely limit its widespread application for admin-
istration to asymptomatic individuals in the context of IPT. A MQ-
like compound that is better tolerated and suitable for single dose
administration would represent a substantial improvement. Such a
compound would need to exhibit equivalent potency and half-life as
MQ , in addition to a lower partitioning into the CNS.
Malaria is a life-threatening disease affecting at least 40% of the
world’s population.1 It originates from several species of the
parasite Plasmodium and claims between 1.5 and 2.7 million lives
annually.2 Plasmodium falciparum (Pf) and Plasmodium vivax
(Pv) cause approximately 90% of cases, with acute falciparum
accounting for most fatalities because of sequestration.3 In field
trials, mefloquine exhibited cure rates of at least 88% and was
better tolerated than quinine.4 Mefloquine (MQ) would be the
U.S. Army’s drug of choice for prophylaxis except for its associa-
tion with neurological effects. Current therapeutic justification
for use of MQ include its long half-life, allowing a weekly dosing
regimen, and its activity against chloroquine-resistant strains.5 The
mechanism of resistance to MQ is known to involve elevated
pfmdr1, yet the agent remains effective in combination with
artesunate.6 For prophylaxis, it is effective everywhere except in
the border regions of Thailand, and it is likely that a combination
with other antimalarials could be developed to address this
shortcoming.
The objective of this lead optimization program is to identify a
next generation quinoline methanol (NGQM) that could
Received: May 20, 2011
Published: August 22, 2011
r
2011 American Chemical Society
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As a first step in this direction, our prior studies attempted to
(1) determine the effect of changes in physiochemical properties
associated with CNS penetrability on potency, (2) show that the
quinoline methanol scaffold provides sufficient chemical space to
identify derivatives with reduced brain uptake, (3) clarify the
screening strategy in order to predict reduced brain penetration
and adverse CNS side-effects, and (4) determine whether any of
the early leads could be optimized and transitioned forward. In an
effort to tackle objective 1, compounds were constructed to
encompass a large range of physicochemical properties and
chemical diversity.4 In terms of physicochemical properties,
lower polar surface area, lower molecular weight, more rotatable
bonds, and fewer H-bond acceptors (HBAs) were associated
with greater potency. There was no such relationship between
activity and log P, log D, or the number of hydrogen bond donors
(HBDs). The addition of a HBD to the side chain yielded a series
of active diamines, which were as metabolically stable as MQ and
showed reduced permeability across MDCK cell monolayers.5
In order to determine whether it was feasible to synthesize
more potent quinoline methanol compounds while retaining the
physicochemical properties associated with acceptable brain uptake
(objective 2), representative compounds were chosen for a proof of
concept study to determine if substituents on the quinoline
methanol scaffold could be modified to allow a reduction in brain
uptake. We found that permeability across MDCK cell monolayers
could be utilized as an in vitro surrogate of in vivo brain uptake
relative to MQ. Therefore, a tiered strategy for assessing the risk of
CNS effects based on in vitro permeability across MDCK cell
monolayers, in vivo brain uptake, and then neurobehavioral screens
in rodents was proposed to address objective 3.6
As shown in Figure 1, four lead scaffolds were pursued from
the first library, encompassing variations at the 4-, 6-, 7-, and
8-positions of the quinoline heterocycle. As previously reported,7
pentafluorosulfanyl analogues of MQ exhibited generally equiva-
lent or lower IC50 and IC90 values against four drug resistant
strains of Pf and greater selectivity than MQ.
In the present study, we synthesized and screened a library of
4-position diamine analogues in an attempt to identify late lead
compounds. Substituents were specifically chosen to incorporate
basic functionalities, i.e., primary, secondary, and tertiary dia-
mines. Structurally simple substituents were selected in order to
reduce the costs of goods associated with a subsequent develop-
ment candidate. We employed a primary in vitro testing cascade
involving in vitro susceptibility screening against two drug-
resistant strains of Pf (MQ resistant D6 and multiple drug-
resistant C235) and a MDCK permeability assay that we showed
previously to be a reasonably effective assay for triaging com-
pounds likely to have higher brain levels than MQ after intrave-
nous dosing in FVB mice. Potential late leads were selected on
the basis of exhibiting IC90 < 100 ng/mL against at least one
strain of Pf together with an apparent permeability of <7.4 Â
10À6 cm/s in the AÀB direction across MDCK monolayers. The
latter threshold was established as being indicative of lower CNS
concentrations of MQ in our earlier work.6
’ RESULTS
The 4-position diamine library 4 was constructed from
epoxide scaffold 3 utilizing a versatile microwave-assisted nu-
cleophilic ring-opening reaction. Epoxide scaffold 3 was pro-
duced in three steps from commercially available quinoline
alcohol 1 (Scheme 1). Because of synthetic feasibility and cost
of goods, racemic epoxide 3 was utilized to generate material
rapidly for in vitro testing. Once a potential lead was identified,
the enantiopure isomers of 3 were utilized.8 As part of our
recognizance strategy, we engaged in the focused incorporation
of commercially available diamines in order to rapidly explore the
corresponding structureÀactivity relationships.
’ DISCUSSION
In order to determine whether any of the early leads could be
transitioned forward or optimized (objective 4), a second-generation
Figure 1. Mefloquine and 4-, 6-, 7-, and 8-position lead scaffolds.
Scheme 1. Synthesis of Quinoline Methanol 4-Position Diamine Librarya
a Reagents and conditions: (a) POBr3, 75À150 ꢀC, 2 h, 91%; (b) (i) Pd2(dba)3, P(t-Bu)3, toluene, tributylvinylstannane, 4 h, 62%; (ii) m-CPBA, K2CO3,
CH2Cl2, reflux overnight, 74%; (c) HNR2, absolute ethanol, microwave for 15 min hold time (150 W, 275 psi, 130 ꢀC, stirring, no cool), R = H,
alkylamines, pyrrolidines, piperidines, and bicyclic diamines.
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Table 1. Antimalarial Activity and Permeability of Piperidine, Pyrrolidine, and Bicyclic Amine Quinoline Methanols14,a
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Table 1. Continued
a D6 is a chloroquine sensitive but mefloquine resistant strain of African origin. C235 is a multiple drug resistant strain of Thai origin. TM91C235 is
resistant to mefloquine, chloroquine, and pyrimethamine. TM90C2A is a two-pfmdr1-copy strain that is also resistant to mefloquine, chloroquine, and
pyrimethamine. W2 is chloroquine resistant and mefloquine sensitive. Papp in AÀB direction in Â10À6 cm/s. ND = no data
Table 2. Antimalarial Activity and Permeability of Dimeric Amine Quinoline Methanolsa
a D6 is a chloroquine sensitive but mefloquine resistant strain of African origin. C235 is a multiple drug resistant strain of Thai origin. TM91C235 is
resistant to mefloquine, chloroquine, and pyrimethamine. TM90C2A is a two-pfmdr1-copy strain that is also resistant to mefloquine, chloroquine, and
pyrimethamine. W2 is chloroquine resistant and mefloquine sensitive. Papp in AÀB direction in Â10À6 cm/s. ND = no data.
library was constructed to systematically explore the chemical space of
the lead diamine series. Although the mechanism of action associated
with MQ remains elusive, we have shown that remarkably small
variations of the 4-position diamine moiety alter the in vitro potency.
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Table 3. Antimalarial Activity and Permeability of N-Substituted “Straight Chain” Ethylenediamine Quinoline Methanolsa
a D6 is a chloroquine sensitive but mefloquine resistant strain of African origin. C235 is a multiple drug resistant strain of Thai origin. TM91C235 is
resistant to mefloquine, chloroquine, and pyrimethamine. TM90C2A is a two-pfmdr1-copy strain that is also resistant to mefloquine, chloroquine, and
pyrimethamine. W2 is chloroquine resistant and mefloquine sensitive. Papp in AÀB direction in Â10À6 cm/s. ND = no data.
Table 4. Antimalarial Activity and Permeability of r-Methyl Substituted and gem-Dimethyl Substituted “Straight Chain”
Ethylenediamine Quinoline Methanolsa
a D6 is a chloroquine sensitive but mefloquine resistant strain of African origin. C235 is a multiple drug resistant strain of Thai origin. TM91C235 is
resistant to mefloquine, chloroquine, and pyrimethamine. TM90C2A is a two-pfmdr1-copy strain that is also resistant to mefloquine, chloroquine, and
pyrimethamine. W2 is chloroquine resistant and mefloquine sensitive. Papp in AÀB direction in Â10À6 cm/s. ND = no data
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Table 5. Antimalarial Activity and Permeability of “Straight Chain” Ethylene Diamine Quinoline Methanolsa
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Table 5. Continued
a D6 is a chloroquine sensitive but mefloquine resistant strain of African origin. C235 is a multiple drug resistant strain of Thai origin. TM91C235 is
resistant to mefloquine, chloroquine, and pyrimethamine. TM90C2A is a two-pfmdr1-copy strain that is also resistant to mefloquine, chloroquine, and
pyrimethamine. W2 is chloroquine resistant and mefloquine sensitive. Papp in AÀB direction in Â10À6 cm/s. ND = no data.
Bicyclic diamine WR319535 (Table 1)9 surfaced as a promis-
ing compound from the first library5 because of the low perme-
ability and favorable pharmacokinetic profile but lacked potency
relative to MQ. In order to explore variations of this analogue, we
constructed a series of pyrrolidine, piperidine, and bicyclic ethy-
lenediamines. Pyrrolidine- and piperidinediamines WR308592
and WR308621emerged asa promising leads thatmetthepotency
benchmarks; unfortunately, these compounds did not exhibit
reduced permeability across MDCK cell monolayers. Morpholine
derivative WR308783 met both potency and permeability bench-
marks and has emerged as a promising compound for future
pharmacokinetic studies. Interestingly, structural isomers WR62-
1193, WR621209, and WR621211 exhibited varied in vitro activity
with comparable permeability across MDCK monolayers. In
regard to the bicyclic compounds constructed, none met both
the potency and permeability benchmarks. These findings, along
with the increased cost of goods associated with a bicyclic diamine
development candidate, steered efforts away from this series.
A series of dimers (Table 2)9 were constructed, and compound
5 (WR319691) emerged asa promising lead since the potency was
comparable to MQ and the permeability across MDCK cell
monolayers was 0.14 Â 10À6 cm/s. Interestingly, the dimers with
tertiary and secondary amines were more potent than those with
two tertiary amines, further illustrating the need for HBDs.
WR319775 and 5 were selected for further evaluation, and the
drug metabolism, pharmacokinetics, maximum brain levels, and
half-life of 5 have recently been disseminated.10
Another approach involved alkyl substitution on the amine
vicinal to the hydroxyl group (Table 3).9 In this series, WR319762
met the permeability criteria but was slightly less potent than MQ.
Another compound, WR319670, was explored because of in vivo
efficacy, an interesting PK profile, and potential as a prodrug. A full
account of this endeavor will soon be disseminated. In regard to
the series of R-substituted ethylenediamines (Table 4),9 none met
both the potency and permeability criteria. From a SAR stand-
point, the addition of an R-methyl substituent increased potency
(compare WR319756 to WR319728). Unfortunately, in these
examples, the increase in potency was mirrored by an increase in
permeability which led us to abandon this approach.
Unlike the R-substituted straight-chain diamines, potency (as
measured by IC90) did not correlate with permeability for the
unsubstituted straight-chain diamineseries. As shown inTable5,9
cyclopropylethylenediamine 6 (WR319749) was more potent in
vitro than tert-butyl ethylenediamine WR319750 but less perme-
able across MDCK cell lines. The presence of a cyclobutyl moiety
in WR621190 resulted in similar potency to 6 but demonstrated
an increase in permeability across MDCK cell lines. This could
indicate an interaction with a specific target rather than an effect
of physiochemical properties on permeability across parasite
membranes. Focusing on the IC90 associated with D6 (MQ
resistant strain of African origin) of the unsubstituted straight-
chain diamines, two compounds (WR308396 and WR319629)
demonstrated increased or equal potency to MQ (D6 IC90
e
25 ng/mL), while eight were less permeable than MQ (MDCK
P
app e 9.3 Â 10À6 cm/s) across MDCK cell lines. Compounds
had acceptable in vitro potency, D6 IC90 e 50 ng/mL, and perme-
ability across MDCK cell lines, MDCK Papp e 9.3 Â 10À6 cm/s.
Although sulfonamide WR319664 was abandoned because of
metabolic stability issues, 6 offered a favorable balance of potency
and permeability.
We elected to further evaluate potential late lead 6 as pure
enantiomers, since development of a racemate presents addi-
tional regulatory burdens unless the individual enantiomeric
components are pharmacologically identical.11 The enantiomers
of MQ exhibit quite different pharmacokinetic properties,12 so
we speculated that this might be the same with related quinoline
methanols. The pure enantiomers of 6 were constructed using
enantiopure epoxides 7 and 88 to provide 10 (WR621308) and
11 (WR621310) (Figure 2). Slow evaporation of a methanol
solution of 7 afforded crystals suitable for X-ray diffraction
analysis (Figure 3), which allowed for structural confirmation.
We selected compound 10 for further studies based on first pass
IC90 screening suggesting moderately greater in vitro potency,
although subsequent multiple replicate testing did not suggest a
major difference in potency between the two enantiomers
(Table 6).9 Compound 10 exhibited modestly lower potency
than MQ across a panel of drug resistant Pf strains, and there
appears to be a pattern of cross-susceptibility between the two
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Table 7. In Vivo Efficacy of 10 Compared to Mefloquine after
Single-Dose Administration in Mice with an Established
Plasmodium berghei Infection
mean survival time (days)/% survival/% cure (N)
dose (mg/kg)
mefloquine
10
vehicle
5
6À8/0/0 (30)
17/20/20 (5)
15/0/0 (5)
6À7/0/0 (5)
6.6/0/0 (5)
6.6/0/0 (5)
6.8/0/0 (5)
10/0/0 (5)
16/0/0 (5)
19/0/0 (5)
30/100/80 (5)
10
20
22/30/10 10)
26/56/36 (25)
28/70/30 (10)
27/50/20 (10)
24/60/50 (10)
40
80
160
320
Figure 2. Synthesis of enantiopure 10 and 11.
Figure 4. Potency (IC90 against Pf D6) of straight chain ethylene
diamine quinoline methanols is not correlated with permeability
(MDCK Papp AÀB).
Figure 3. X-ray structure of 7.
scaling factor to allow for species differences in body surface area.13
After single dose administration in mice, compound 10 cured four of
five mice with an established Plasmodium berghei infection at a dose
of 320 mg/kg po without evidence of toxicity. While MQ is more
active at lower doses, the same cure rate is not observed until a dose
of 320 mg/kg po is reached, and this dose level is associated with
toxicity in some instances (Table 7).9 Collectively these data suggest
we identified a compound that is curative after single dose admin-
istration and has a longer half-life, lower partitioning into the CNS,
and an improved cardiac safety index relative to MQ.
Table 6. In Vitro Potency of 10 and 11a
average IC90 ( STDEV in ng/mL (n = 3)
compd
Pf W2
Pf D6
Pf C235
Pf C2A
mefloquine
chloroquine
10
6.7 ( 2.9
266 ( 132
11 ( 1.5
11 ( 1.6
16 ( 7.8
5.1 ( 2.0
27 ( 2.7
37 ( 3.5
53 ( 21
89 ( 28
77 ( 19
103 ( 16
52 ( 27
139 ( 77
73 ( 29
75 ( 12
11
a D6 is a chloroquine sensitive but mefloquine resistant strain of African
origin. C235 is a multiple drug resistant strain of Thai origin. TM91C235
is resistant to mefloquine, chloroquine, and pyrimethamine. TM90C2A
is a two-pfmdr1-copy strain that is also resistant to mefloquine,
chloroquine, and pyrimethamine. W2 is chloroquine resistant and
mefloquine sensitive. Papp in AÀB direction in Â10À6 cm/s.
’ CONCLUSIONS
Several general conclusions can be drawn regarding structureÀ
activity relationships among these diamine quinoline metha-
nols. First, potency (as measured by IC90) did not correlate with
permeability (r2 = 0.14, P = 0.12, Figure 4) for the diamine series.
Second, although the mechanism of action associated with MQ
remains elusive, we have shown that remarkably small variations
of the diamine moiety alter the in vitro potency and permeability
across MDCK cell lines. Compound 5 has emerged as a promis-
ing candidate and has been profiled in a recently published
pharmacokinetic study.10 Racemic 6 met the potency and
permeability benchmarks and was synthesized as pure enantio-
mers (10 and 11) for further evaluation. Compound 10 has been
shown to be as curative as MQ after a single dose in vivo. This
compound could be appropriate for IPTx indications or any
other malaria indication for which MQ is currently provided.
compounds based on this very small panel of isolates. We do not
expect this property to limit clinical utility of this compound in
most parts of the world, and appropriate combination should
ensure its effectiveness in those endemic areas with a background
of resistance to MQ monotherapy.
The efficacy of 10 in mice was evaluated up to a maximum
single orally administered dose (po) of 320 mg/kg (Table 7).9
This dose was selected as the ceiling, since it represents the
approximate mouse equivalent of the human treatment dose of
MQ (25 mg/kg) after application of an appropriate alometric
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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
http://pubs.acs.org.
’ 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
Technology (http://www.registech.com; refer to Supporting Informa-
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,
DC, 2005; http://www.fda.gov/Drugs/GuidanceComplianceRegula-
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:
Washington, DC, 2005; http://www.fda.gov/Drugs/GuidanceCom-
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-
tion of Helsinki. Ther. Clin. Risk Manage. 2008, 4.
(2) Briand, V.; Bottero, J; No€el, H.; Masse, V.; Cordel, H.; Guerra, J.;
Kossou, H.; Fayomi, B.; Ayemonna, P.; Fievet, N.; Massougbodji,
A.; Cot, M. Intermittent treatment for the prevention of malaria
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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