Cyclopropyl carboxamides: A new oral antimalarial series derived from the Tres Cantos Anti-Malarial Set (TCAMS)

Article abstract of DOI:10.1021/ml2001517

Rapid triaging of three series of related hits selected from the Tres Cantos Anti-Malarial Set (TCAMS) are described. A triazolopyrimidine series was deprioritized due to delayed inhibition of parasite growth. A lactic acid series has derivatives with IC₅₀ < 500 nM in a standard Plasmodium falciparumin vitro whole cell assay (Pf assay) but shows half-lives of < 30 min in both human and murine microsomes. Compound 19, from a series of cyclopropyl carboxamides, is a highly potent in vitro inhibitor of P. falciparum (IC₅₀ = 3 nM) and has an oral bioavailability of 55% in CD-1 mice and an ED₉₀ of 20 mg/kg after oral dosing in a nonmyelo-depleted P. falciparum murine model.

Full text of DOI:10.1021/ml2001517

LETTER
pubs.acs.org/acsmedchemlett
Cyclopropyl Carboxamides: A New Oral Antimalarial Series Derived
from the Tres Cantos Anti-Malarial Set (TCAMS)
Lourdes Rueda,† Isabel Castellote,† Julia Castro-Pichel,† Maria J. Chaparro,† Juan Carlos de la Rosa,†
Adolfo Garcia-Perez,† Mariola Gordo,† Maria Belen Jimenez-Diaz,† Albane Kessler,† Simon J.F. Macdonald,^
Maria Santos Martinez,† Laura M. Sanz,† Francisco Javier Gamo,*,† and Esther Fernandez*,†
†Tres Cantos Medicines Development Campus, Diseases of the Developing World (DDW), GlaxoSmithKline,
Severo Ochoa 2, 28760 Tres Cantos, Spain
^Medicines for Malaria Venture, ICC, Route de Pre-Bois, PO Box 1826, 1215 Geneva 15, Switzerland
S Supporting Information
b
ABSTRACT: Rapid triaging of three series of related hits selected from the Tres Cantos Anti-
Malarial Set (TCAMS) are described. A triazolopyrimidine series was deprioritized due to
delayed inhibition of parasite growth. A lactic acid series has derivatives with IC50 < 500 nM in a
standard Plasmodium falciparum in vitro whole cell assay (Pf assay) but shows half-lives of < 30
min in both human and murine microsomes. Compound 19, from a series of cyclopropyl
carboxamides, is a highly potent in vitro inhibitor of P. falciparum (IC50 = 3 nM) and has an oral
bioavailability of 55% in CD-1 mice and an ED90 of 20 mg/kg after oral dosing in a nonmyelo-
depleted P. falciparum murine model.
KEYWORDS: TCAMS, Tres Cantos Anti-Malarial Set, malaria, cyclopropyl, carboxamide,
triazole, oral bioavailability, in vivo activity, murine, Plasmodium falciparum, Medicines for
Malaria Venture
ach year, approximately 250 million people are affected by
In recent years, Novartis,9 Guy at St. Jude's Hospital
Memphis,10 and GlaxoSmithKline11 have made major contribu-
tions toward the search for new antimalarial medicines by
publishing new antimalarial hit structures. GSK published over
13,000 confirmed hits, which inhibit parasite growth by at least
80% at 2 μM concentration; these are known as the Tres Cantos
Antimalarial Compounds Set (TCAMS).11 More than 8,000
show activity against the multidrug-resistant P. falciparum Dd2
strain.11 This is a substantial number of new chemical starting
points for antimalarial lead identification. Both structures and
screening data are available online for public download from the
European Bioinformatics Institute at http://www.ebi.ac.uk/
chemblntd. TCAMS came from screening over 2 million com-
pounds in the GSK corporate collection, and more than 80% of
these are previously proprietary molecules. By putting these
structures into the public domain, GSK hopes to contribute
toward stimulating additional research into the development of
new antimalarial medicines.
E
malaria, and around 800 000 people die. The disease parti-
cularly affects children under 5 and pregnant women1 and is
particularly prevalent in sub-Saharan Africa where the economic
and humanitarian burden is considerable.1 Malaria is caused by
parasites of the genus Plasmodium with Plasmodium falciparum
and Plasmodium vivax being predominantly responsible for
the highest mortality and highest morbidity, respectively.2 Despite
approved treatments for malaria such as quinine (1), chloroquine
(2), coartem [a combination of artemether (3) and lumefantrine
(4)], and malarone [atovaquone (5) and proguanil (6) combina-
tion] (structures provided in the Supporting Information), the
development of clinically resistant P. falciparum strains compro-
mises treatment. Artemisinin-resistant strains are now also begin-
ning to emerge.2 In 2007, the Bill and Melinda Gates Foundation
supported by other global health organizations initiated a malaria
eradication agenda;2 the combination of resistance and the eradi-
cation agenda means that there remains an urgent need for new
antimalarial medicines. Among several compounds under devel-
opment, tafenoquine (7), an analogue of primaquine that origi-
nated from the Walter Reed Army Institute of Research, is an
8-aminoquinoline being developed by GSK in conjunction with
Medicines for Malaria Venture as a radical cure of P. vivax.
A recent review describes medicinal chemistry progress to-
ward new antimalarial medicines,3 while a drug candidate for
malaria from an oxaborole series4 has been announced in the last
year. Numerous chemotypes have also been published, a selec-
tion of which include naphthoquinones,5 nucleosides,6 ureas,7
and endoperoxide-falcipain.8
With over 13,000 starting points for new antimalarials, it is
both a tremendous opportunity and also a challenge to identify
those starting points with the highest quality. Our initial process
involved various computational clustering and filtration techni-
ques and is described elsewhere.12 From this process, we detail
here several series of carboxamides as the first report for
progressing hits identified from TCAMS.
Received: June 21, 2011
Accepted: August 29, 2011
Published: August 29, 2011
r
2011 American Chemical Society
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LETTER
Table 1. Three Related Carboxamide Hit Series
a Molecular weight. b Calculated using Daylight software. c A lipophilicity value measured at pH 7.4 (see the Supporting Information). d Where
applicable, all compounds are racemic. e The XC50 was derived from a 5-fold dilution protocol of the LDH assay as described in ref 11. f See ref 11 for
experimental details of the LDH assay. g P. falciparum 3H-hypoxanthine assay (see the Supporting Information for experimental details and standard
deviations).
One of the significant benefits of these carboxamide series is
that analogues are readily prepared in very few steps. The
compounds described were commercially available or readily
assembled from commercially available acids and anilines using
standard amide coupling procedures via the appropriate acid
chloride or using coupling reagents. The heterocyclic substitu-
ents were introduced by copper(I) iodide-mediated coupling of
the appropriate aryl bromide and the heterocycle often with
8-hydroxyquinoline catalysis (see the Supporting Information).
Different assays were used to assess in vitro growth inhibition of
P. falciparum 3D7 parasites. The high-throughput screen (HTS)
used to identify TCAMS compounds used parasite lactate dehy-
drogenase (LDH) as a surrogate of Plasmodium growth.11 Esti-
mates of compound concentration producing 50% inhibition of
parasite growth were obtained for TCAMS using 5-fold dilutions
down to 3 nM, and these values are designated as “XC50’s”
(Table 1).11 IC50 values that were more accurately determined
than XC50 values were calculated from full doseÀresponse curves
using 3-fold dilution and are designated LDH IC50 values
3
(Table 1).11 The standard H-hypoxanthine whole cell assay
(abbreviated to Pf assay) was used to generate IC50 values
for the determination of structureÀactivity relationship (SAR)
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LETTER
Table 2. SAR for Lactic Acid Ethers (Series 2)
mouse microsomes
human microsomes
compd no.
Ra
MWtb
376.3
clog Pb CHIb
Pfb IC50 (μM)
CLic (mL/min/g)
t1/2 (min)
CLic (mL/min/g)
2.9
t1/2 (min)
15
H
3.44
3.52
4.06
3.71
4.29
3.84
4.29
3.84
4.57
0.897
5.3
5.6
7.9
4.1
12.0
24.7
16
17
12
18
2-Cl
3-Cl
4-Cl
3-CF3
410.8
410.8
410.8
444.3
0.190
0.327
0.394
0.285
11.7
6.2
1.6
1.2
3.3
>30
>30
21.8
13.6
a All compounds racemic where applicable. b See Table 1 for abbreviations. c In vitro intrinsic clearance.
(Tables 1À3).13 Most of the compounds described herein showed
no or very little activity against mammalian cells in a standard
cytotoxicity assay using a HepG2 cell line that is a widely used
in vitro marker for liver toxicity (data not shown).14
assay.11 However, when tested in the hypoxanthine assay, these
compounds displayed only weak activity or were inactive, which
from subsequent experiments was indicative of a delayed death
phenotype (see the Supporting Information). As a rapid onset of
action is desirable for first-line treatments, no further work was
therefore carried out on series 1.
After careful computational analysis of TCAMS,12 three
related carboxamide “hit” series were identified for further
profiling (Table 1). All of the members of the series display as
a common feature a trisubstituted left-hand (LH) aromatic ring
linked through an amide to right-hand (RH) aromatic ring. The
spacing between these aromatic rings is approximately similar but
achieved in different ways by variation of the carboxylic acid
fragment of the amide. Series 1 (referred to as the “triazolopyr-
imidine” series) features a bicyclic triazolopyrimidine carboxylic
acid fragment (8 and 9), series 2 (referred to as the “lactic acid
ether” series) features an aryloxy-lactic acid fragment (10À12),
and series 3 (referred to as the “cyclopropyl carboxamide” series)
features an arylcyclopropyl-acetic acid fragment (13 and 14).
These series were immediately appealing as potential starting
points for oral drug discovery programmes because of their
relatively low molecular weights (339À429), lipophilicity (clog
P 2.48À4.72), and hydrogen bond acceptor and donor counts.
The series are also all synthetically tractable, which is important
both for rapid lead optimization and in reducing potential cost of
goods, which is crucial where the target cost per treatment for an
adult is less than $1 and for a child less than $0.50. Less appealing
was the potential for aniline metabolites, but in most cases, the
amide bond is sterically hindered, which might prevent or retard
metabolism.
The lactic acid ethers of series 2 can be viewed as bioisosteres
of series 1 where the triazole ring of the bicycle has been ring
opened. From the data (Table 1), these do not suffer from the
delayed killing phenotype of series 1. Methyl or chloro substitu-
tion is tolerated on the RH ring (ring C) (compounds 10 vs 11
and 12), while the morpholine substituent of ring B (11) can be
replaced by a triazole substituent (12) without affecting the
potency, but it does reduce the measured lipophilicity (CHI
logD15) from 4.56 to 3.84. By inference from series 3, the
trifluoromethyl group on ring B was likely to be preferred. As a
result of these SAR together with the ready commercial avail-
ability of substituted aryloxy lactic acids, we initially explored the
activity of substituents on ring C (Table 2) and on the carbon α
to the amide carbonyl (see the Supporting Information). How-
ever, we were both unable to significantly increase potency, and
the active members of the series possessed only short half-lives in
mouse microsomes (Table 2 and the Supporting Information).
These data, together with the indication that a chiral center might
be required, led to further work on this series 2 being put on hold.
In addition, analogues of the cyclopropyl carboxamide series 3,
which were being prepared at the same time, were demonstrating
profiles that were showing greater promise.
Our initial strategy was to establish preliminary SAR for all
three series with the ultimate aim of determining which series was
the most promising for full lead optimization. To ensure that this
was achieved as rapidly as possible, we focused on generating and
testing those analogues that were most synthetically accessible.
This left gaps in the SAR but, in our view, did not significantly
affect the quality of decisions that were made.
The cyclopropyl carboxamide series 3 (Table 1) is the most
potent of the three series with 13 having a Pf IC50 of 66 nM. Like
series 2, it also features a triazole substituent on the B ring while
also incorporating a benzylic cyclopropyl group adjacent to the
amide. The trifluoromethyl substituent on ring B of 13 is 25
times more active than the corresponding chloro analogue 14.
The lipophilicity (CHI logD 3.83) and molecular weight (372)
of 13 also allow modest scope for adding groups while still
remaining within physicochemical space, which is reasonably
The triazolopyrimidines of series 1 (8 and 9) appeared very
potent in vitro P. falciparum inhibitors when using the LDH
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LETTER
compatible with oral absorption. We therefore initiated a brief
but systematic exploration of the SAR for each part of the
molecule, namely, (i) the A ring (the triazole in 13), (ii) the
CF3 substituent in ring B, (iii) the cyclopropyl group adjacent to
the amide carbonyl, and (iv) substitution on the C ring. In
summary, exploration of iÀiii gave no improvement in the overall
properties of the series (see the Supporting Information).
However, a wide variety of substituents were explored in
optimization of the substitution on the C ring (see the Support-
ing Information) and the electronic and lipophilic nature of 19—
featuring a m-CF3—proved highly beneficial with a 30-fold
increase in activity with a Pf IC50 of 3 nM (Table 3). As a next
step, we therefore embarked on a fuller profiling of the leads 13
and 19 (Table 3), including pharmacokinetic and efficacy studies,
prior to initiating full lead optimization.
The pharmacokinetic profiles of both 13 and 19 were eval-
uated in CD-1 mice (Table 4). Following intravenous adminis-
tration to CD-1 mice, compounds 13 and 19 were characterized
by a moderate clearance (1/10À3/4 liver blood flow) and a high
volume of distribution. The estimated terminal half-life was high
for 13 and very high for 19. A high oral bioavailabity was
calculated after the oral gavage administration of 20 mg/kg for
both compounds (see the Supporting Information).
Both compounds displayed in vivo efficacy after oral dosing in
a nonmyelo-depleted P. falciparum murine model.17,18 Briefly,
groups of three mice engrafted with human erythrocytes were
injected with 20 Â 106 P. falciparum-infected erythrocytes per
mouse. Three days after infection, mice were treated with vehicle
and compounds 13 and 19. Parasitemia in peripheral blood was
assessed from day 3 to day 7 (Figure 1). Both compounds
inhibited P. falciparum growth in vivo with estimated efficacies
expressed as ED90 values of >50 and 20 mg/kg for 13 and 19,
respectively. Chloroquine was used as the control and has an
ED50 of between 2 and 5 mg/kg (from 24 experiments). By way
of comparison, the ED50 values of 13 and 19 are >50 and 12 mg/kg,
respectively.
Described herein is the first report of exploration of lead
series selected from the TCAMS. Initial SAR exploration of three
carboxamide series led to the rapid deprioritization of two of the
series. In contrast, a cyclopropyl carboxamide series displayed
promising properties in particular possessing good oral bioavail-
ability in CD-1 mice and also in vivo activity with the ED50 of 19
being only 2À3 times higher than that of chloroquine under
these conditions, although additional studies would be needed to
assess the real potential for curing malaria. As such, it represents a
The overall profiles of both 13 and 19 are reasonable;14
however, improving the solubility will help developability. Re-
ducing the plasma protein binding might decrease the ultimate
clinical dose although both compounds have promising in vivo
activity (see later) despite the very high protein binding ob-
served. Improving selectivity over the PXR receptor and PDE4B
would also be beneficial.16
Table 3. Physicochemical and in Vitro Profiles of 13 and 19
property/assaya
MWt
13
19
372.4
3.49
3.83
0.066
>10c
>50
440.3
4.38
4.25
0.003
>10d
>50
9
clog P
CHI
Pf IC50 (μM)
cP450b (μM)
hERGe (μM)
CLND solubilityf (μM) 100
permeability (nM/s)
mouse ppbg (%)
human ppb (%)
cross-screening
240
99.0
99.0
99.4
inactive in 44/45 assaysh inactive in 43/45 assaysi
a See previous tables for definitions of abbreviations. b P450s tested were
2C9, 2C19, 2D6, and 3A4. c Except for 2C9 7.9 μM. d Except for 2C9 6.3
μM. e Dofetilide binding assay. f Chemiluminescent nitrogen detection—a
turbimetric assay from DMSO solution. g Ppb is a plasma protein binding.
h A 2.5 μM activity observed against the PXR receptor. i A 0.3 and 1 μM
activity observed against PDE4B and the PXR receptor.
Figure 1. Plot of compound dose (chloroquine 2, 13, and 19) vs log10
(% parasitemia) after oral administration. See the text for assay details
and estimated ED50 and ED90 values.
Table 4. Pharmacokinetic Parameters for 13 and 19 Estimated in Blood in CD-1 Micea
area under curve AUC0-t (μg/h/mL)
clearance
volume of
half-lifeb
(h)
maximum concn
Cmaxc (μg/mL)
oral
compd no.
(mL/min/kg)
distribution (L/kg)
iv
po
bioavailability (% F)
13d
19e
29.7
14.3
6.47
11.9
2.77
10.2
2.34
1.09
0.596
2.23
9.71
81
55
13.6
a Dosing 2 mg/kg iv and 20 mg/kg po into CD-1 mice (n = 4 for both arms). b iv. c po. d iv vehicle 20% (v:v) encapsine in water, po vehicle 1% (w:v)
methylcellulose in water. e iv vehicle 3% solutol, 7% PEG (v:v) in saline, po vehicle 1% (w:v) methylcellulose in water.
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LETTER
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Further studies on this series have been carried out, and details
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’ ASSOCIATED CONTENT
S
Supporting Information. Further experimental details.
b
This material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Corresponding Author Email address: esther.p.fernandez@
gsk.com. Phone: +34-918070551. Fax: +34-91-8070550.
Funding Sources
(11) Gamo, F.-J.; Sanz, L. M.; Vidal, J.; de Cozar, C.; Alvarez, E.;
Lavandera, J.-L.; Vanderwall, D. E.; Green, D. V. S.; Kumar, K.; Hasan,
S.; Brown, J. R.; Peishoff, C. E.; Cardon, L. R.; Garcia-Bustos, J. F.
Thousands of chemical starting points for antimalarial lead identifica-
tion. Nature 2010, 465, 305–310.
GlaxoSmithKline acknowledges financial support from Medi-
cines for Malaria Venture (MMV) and for the perceptive and
helpful advice from Jeremy Burrows and Mike Witty.
(12) Calderꢀon, F.; Barros, D.; Bueno, J. M.; Coterꢀon, J. M.;
Fernꢀandez, E.; Gamo, F. J.; Lavandera, J. L.; Leꢀon, M. L.; Macdonald,
S. J. F.; Mallo, A.; Manzano, P.; Porras, E.; Fiandor, J. M.; Castro, J.
An Invitation to Open Innovation in Malaria Drug Discovery: 47
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DOI: 10.1021/ml200135p.
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Nature Rev. Drug Discovery 2004, 3, 509–520.
’ ACKNOWLEDGMENT
We thank our colleagues from the Computational, Analytical
and Structural Chemistry (CASC) department for the measure-
ment of the physicochemical properties of compounds described
in this paper.
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