Advancement of imidazo[1,2-a]pyridines with improved pharmacokinetics and nM activity vs. Mycobacterium tuberculosis

Article abstract of DOI:10.1021/ml400088y

A set of 14 imidazo[1,2-a]pyridine-3-carboxamides was synthesized and screened against Mycobacterium tuberculosis H₃₇Rv. The minimum inhibitory concentrations of 12 of these agents were ≤1 μM against replicating bacteria and 5 compounds (9, 12, 16, 17, and 18) had MIC values ≤0.006 μM. Compounds 13 and 18 were screened against a panel of MDR and XDR drug resistant clinical Mtb strains with the potency of 18 surpassing that of clinical candidate PA-824 by nearly 10-fold. The in vivo pharmacokinetics of compounds 13 and 18 were evaluated in male mice by oral (PO) and intravenous (IV) routes. These results indicate that readily synthesized imidazo[1,2-a]pyridine-3-carboxamides are an exciting new class of potent, selective anti-TB agents that merit additional development opportunities.

Full text of DOI:10.1021/ml400088y

Letter
pubs.acs.org/acsmedchemlett
Advancement of Imidazo[1,2‑a]pyridines with Improved
Pharmacokinetics and nM Activity vs. Mycobacterium tuberculosis
Garrett C. Moraski,† Lowell D. Markley,† Jeffrey Cramer,‡ Philip A. Hipskind,‡ Helena Boshoff,§
Mai A. Bailey,∥ Torey Alling,∥ Juliane Ollinger,∥ Tanya Parish,∥ and Marvin J. Miller*,†
†Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
‡Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States
§Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases,
National Institutes of Health, Bethesda, Maryland 20892, United States
∥Infectious Disease Research Institute, 1616 Eastlake Ave E, Suite 400, Seattle, Washington 98102, United States
S
* Supporting Information
ABSTRACT: A set of 14 imidazo[1,2-a]pyridine-3-carbox-
amides was synthesized and screened against Mycobacterium
tuberculosis H37Rv. The minimum inhibitory concentrations of
12 of these agents were ≤1 μM against replicating bacteria and
5 compounds (9, 12, 16, 17, and 18) had MIC values ≤0.006
μM. Compounds 13 and 18 were screened against a panel of
MDR and XDR drug resistant clinical Mtb strains with the potency of 18 surpassing that of clinical candidate PA-824 by nearly
10-fold. The in vivo pharmacokinetics of compounds 13 and 18 were evaluated in male mice by oral (PO) and intravenous (IV)
routes. These results indicate that readily synthesized imidazo[1,2-a]pyridine-3-carboxamides are an exciting new class of potent,
selective anti-TB agents that merit additional development opportunities.
KEYWORDS: Mycobacterium tuberculosis, imidazo[1,2-a]pyridine-3-carboxamides, MDR-TB, XDR-TB, pharmacokinetics
uberculosis (TB) is a serious global health problem caused
imidazo[1,2-a]pyridine-3-carboxylic acid intermediates were all
Tby the bacterium Mycobacterium tuberculosis (Mtb). More readily converted to various amide analogues (5−19) through
classical EDC-mediated coupling reactions (55% for 7,
unoptimized).
than one-third of the world’s population is infected with TB and
that resulted in an estimated 1 400 000 deaths worldwide in
2010.1 With someone dying of TB nearly every 20 s, and an
increase in cases of drug resistant TB, there is an urgent need for
discovery and development of new treatments. Herein we report
on the additional structure activity relationship (SAR) studies on
the imidazo[1,2-a]pyridine-3-carboxylate scaffold that we
disclosed2−4 and has since been identified and profiled by
other groups.5−7 Our new studies described herein have
produced compounds with dramatically enhanced (low nano-
molar) potency and significantly enhanced pharmacokinetics
(PK).
We prepared five different imidazo[1,2-a]pyridine-3-carbox-
ylic acid intermediates (3a−3e), which were elaborated into a
focused set of antitubercular agents (5−19) with generalized
structure 4. These compounds were easily made in straightfor-
ward syntheses in good overall yields (Scheme 1). First, reaction
of the appropriately substituted 2-aminopyridine (1) with ethyl
2-chloroacetoacetate followed by saponification with lithium
hydroxide and acidic work up gave the free acids 3a−3d. Use of
the same procedure but starting with 2-amino-5-methylpyridine
(1) and ethyl 2-chloro-4,4,4-trifluoroacetoacetate (2, R2CF3)
followed by saponification and acidic work up gave free acid 3e
(87% yield). It should be noted that while carboxylic acids 3a−3d
can all be prepared by the general method described; they also
are commercially available, while 3e was not. Finally, these
SAR studies resulted in a panel of 14 new imidazo[1,2-
a]pyridine-3-carboxamide analogues (6−19) for evaluation. A
schematic grouping of the analogues produced is provided in
Scheme 2. The initial “hit” compound 5 was previously evaluated
as active using the MABA for Mtb;2 we rescreened this
compound using an alternative minimal inhibitory concentration
(MIC, defined as the concentration that prevents >99% of
bacterial growth at 5 days post inhibitor exposure) assay to
confirm activity.4 We found that 5 had a slightly lower MIC (0.2
μM) in this assay compared to the MIC range using MABA in
various media (0.8−2.3 μM).2 It is possible this is due, in part, to
the use of an alternative medium as this assay uses glucose as a
carbon source which is different from that used in the MABA
assays. Initially, the SAR focus was to make compounds with
lower cLog P values than compound 5 (clogP of 3.6) in the hope
that the more polar compounds would be substantially more
potent through favorable interactions and also be more soluble.8
Therefore, sulfonamide (6), sulfonyl (7 and 8), and 2-pyridyl
(13) compounds were made and screened. Compound 9 is a
positional isomer of compound 5 while compound 12
Received: March 4, 2013
Accepted: May 17, 2013
© XXXX American Chemical Society
A
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ACS Medicinal Chemistry Letters
Letter
diversity to this series. Compounds 11, 16−19 were made to
explore possible size limitations of having biaryl ether amides and
further expanded upon the chemical diversity screened within
this class.
Scheme 1. General Synthesis of Imidazo[1,2-a]pyridine-3-
carboxamides
a
Table 1 summarizes the in vitro antitubercular activity of these
15 analogues against Mtb H37Rv grown using glucose as a carbon
Table 1. In Vitro Evaluation of Compounds 5−19, Two
Controls, and Two Clinical Candidates against Replicating
Mtb H37Rv (μM)
MIC (μM)
a
cmpd
MW
ClogP
avg
0.2
SD
0.2
5
6
7
8
9
279.34
358.41
411.40
357.43
279.34
295.34
425.40
322.18
382.77
329.78
409.84
405.88
389.42
389.42
389.42
822.94
137.14
431.39
359.26
3.60
1.76
1.75
1.95
3.60
3.34
6.40
3.76
3.13
3.74
6.06
6.41
5.84
5.84
5.84
6.04
−0.67
2.45
2.80
>20
0.9
ND
0.3
0.4
0.1
0.006
>20
0.7
0.003
ND
10
11
0.4
12
0.05
0.7
0.008
0.1
13
14
1.1
0.4
15
0.02
0.006
0.005
0.004
0.1
0.009
0.004
0.002
0.002
0.02
0.006
0.02
0.001
0.1
16
17
18
19
rifampicin
isoniazid
0.003
0.3
b
BTZ043
0.003
0.6
a
c
Reagents: (a) ethyl 2-chloroacetoacetate (for 3a−3d) and ethyl 2-
PA-824
chloro-4,4,4-trifluoroacetoacetate (for 3e), DME, reflux, 48 h; (b) (1)
a
ClogP calculated by ChemDraw version 12.0; MICs are the
LiOH, EtOH, (2) HCl, 56 h; (c) EDC, DMAP, R3, CH3CN, 16 h.
minimum inhibitory concentration required to inhibit growth by
>99%. Mtb was grown in Middlebrook 7H9 medium supplemented
with OADC (oleic acid, BSA, glucose, catalase) and 0.05% Tween 80
using two readouts of growth (optical density and fluorescence) as
described.4 SD = standard deviation; ND = not determined values
reported are the average of MICs generated with both readouts from a
Scheme 2. Grouping of Imidazo[1,2-a]pyridine Analogues
b
minimum of two independent runs. A gift from Alere Technologies
c
GmbH and Alere Inc. Obtained from PracticaChem LLC.
source. All compounds evaluated were very potent (MIC < 2
μM) with the exception of the sulfonamide (6, MIC > 20 μM)
and the aniline-derivative (10, >20 μM). Previous work with
pyrimidine-imidazoles had suggested that similar types of
compounds might have a glycerol-dependent effect.9 We
eliminated any concern that the activity of these compounds
might be glycerol-dependent by evaluating compounds 5 and 18
against Mtb grown with and without glycerol as an additional
carbon source. In fact, the MICs of both compounds 5 and 18
were lower (3 and 4-fold, respectively), in the absence of glycerol
(see the Supporting Information). This confirmed that glycerol
metabolism was not responsible for the potency of these
compounds. We can also rule out concerns of high protein
binding as a set of compounds was run with and without the
addition of bovine serum albumin (BSA) and no shift in MIC was
observed (see the Supporting Information). Additionally, the
toxicity against the Hep2G cell line was determined for
compounds 11, 12, 16, and 15 and a large therapeutic window
was observed (IC50 > 50 μM, respectively; see the Supporting
Information).
incorporates the basic dimethylaniline moiety. Neither com-
pound 9 nor 13 lowered the cLog P but they did add chemical
B
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ACS Medicinal Chemistry Letters
Letter
Table 2. MDR- and XDR-Mtb Activity of Compounds 13 and 16 and Control PA-824
compound MIC μM (μg/mL)
a
strain
DS- Mtb1
DS- Mtb2
9
13
18
PA-824
0.04−0.07 (0.01−0.02)
<0.04 (<0.01)
<0.04 (<0.01)
<0.04 (<0.01)
2.3 (0.63)
0.8 (0.3)
<0.03 (<0.01)
0.5−0.9 (0.2−0.3)
>13.9 (>5)
0.8 (0.3)
<0.03 (<0.01)
b
b
MDR-Mtb HREZSKP
MDR-Mtb HREKP
MDR-Mtb HRERb
XDR-Mtb HRESKO
XDR-Mtb HREKO
6.5 (2.5)
0.03−0.8 (0.01−0.3 )
<0.03 (<0.01)
0.80 (0.31)
0.5−0.9 (0.2−0.3)
0.5−0.9 (0.2 −0.3)
0.5−0.9 (0.2−0.3)
0.9 (0.3)
0.4 (0.2)
13−26 (5−10)
0.8 (0.3)
<0.04 (<0.01)
<0.04 (<0.01)
<0.03 (<0.01)
<0.03 (<0.01)
0.8 (0.3)
0.2 (0.08)
a
DS-Mtb1 = drug sensitive clinical isolate no. 1; DS-Mtb2 = drug sensitive clinical isolate no. 2; MDR-Mtb = multidrug resistant Mtb; XDR-Mtb =
extensively drug resistant Mtb; drugs abbreviated as H = isoniazid, R = rifampin, E = ethambutol, Z = pyrazinamide, S = streptomycin, K =
b
kanamycin, P = p-aminosalicylic acid, Rb = rifabutin, O = ofloxacin. Growth inhibited >90% up to 0.8 μM (0.3 μg/mL). MICs are the minimum
concentration required to inhibit growth by >99%; MICs were done in 7H9/glucose/glycerol/BSA/0.05% Tween 80 and the average of three
individual measurements.
The SAR analysis based on the whole cell assay readouts
indicated that while some polar compounds (7 and 8, MIC = 0.9
and 0.4 μM; clog P 1.8 and 2, respectively) did retain good
activity, others did not (6, MIC > 20 μM; clog P 1.8). This keeps
the question of whether increased polarity will yield increased
potency open for further SAR studies. The substitution of the 7-
methyl with the 7-chloro group on the imidazo[1,2-a]pyridine
core appeared to diminish activity by 5-fold when 18 is compared
to 15 (MIC = 0.004 and 0.02 μM, respectively).
Most apparent was that the larger, more lipophilic biaryl ethers
had nanomolar potency. Indeed, independent of whether the
substitution on the biaryl ether was a chlorine (16) or fluorine
(18), potency was outstanding (MIC = 0.006 and 0.004 μM,
respectively). Interestingly, the position of the methyl group
might play a role in potency as the 8-methyl analogue (19) was
much less potent (MIC = 0.1 μM) than the other isomeric 6- and
7-methyl analogues (17 and 18, respectively) which were nearly
equipotent (MIC = 0.005 and 0.004 μM, respectively). The
possible effect of position of the methyl group is seen more
dramatically by comparing compounds 5 and 9, where
compound 9 (MIC = 0.004 μM) was much more potent than
its positional isomer, compound 5 (MIC = 0.2 μM). This again
suggests that the position of the methyl group may play a role in
potency as the 6-methyl was considerably more active than the 7-
methyl analogue. The 2-pyridyl compound, 13, had good
potency (MIC = 0.7 μM) and a lower cLog P value of 3.1.
Moreover, compound 13 was not as susceptible to in vitro and in
vivo metabolism compared to the published values2 for
compound 5, presumably due to the steric and electronic factors
imparted by the pyridine substituents (19% metabolized for 13
compared to 71% for 5 in rat liver microsomes).
Encouraged that 5 of the 14 new analogues tested had low
nanomolar MIC values against the replicating Mtb H37Rv strain,
we screened compounds 9, 13, and 18 against a panel of sensitive,
multidrug resistant (MDR) and extensively drug resistant
(XDR) clinical strains (Table 2) with the nitroimidazole clinical
candidate PA-82410 as the control.
Compound 9 had excellent potency against these clinical
strains (MIC of 0.04−2.3 μM) that was comparable to or slightly
lower than that reported for the isomer (5) which had MICs of
0.07−2.3 μM (against a panel of 12 MDR- and XDR-Mtb
strains).2 Compound 13 had the widest range of activity against
these clinical strains (MICs of 0.4−26 μM) and in general was
not quite as potent as PA-824 (MICs of 0.2 to >14 μM) against
the majority of the drug resistant strains screened.
It did, however, show a different “fingerprint” of inhibition
than PA-824 and was potent (MIC of 0.8 μM) against the drug
sensitive strain that was resistant to PA-824 (MIC > 14 μM),
suggesting a different mechanism of action than PA-824,11 as
would be expected for these structurally different molecules.
Compound 18 was most potent against all the drug resistant
strains screened (MICs of <0.03 to 0.8 μM) and was much more
active than PA-824 in nearly every strain screened with the
exception of the MDR strain “HRERb”, a strain that is resistant to
isoniazid, rifampin, ethambutol, and rifabutin. Against that strain,
18 was about equipotent to PA-824. This outstanding potency
against the various drug resistant strains suggests that this class is
most likely inhibiting a novel and essential target in these clinical
strains. This hypothesis appears to be supported by recent
publications wherein various imidazo[1,2-a]pyridines were
found to be inhibitors of ATP homeoestasis5 by targeting
QcrB, which encodes the b subunit of the electron transport
ubiquinol cytochrome C reductase.6 This single mutation
generated in M. bovis BCG resulted in cross-resistance of three
compounds evaluated by the GSK group and is therefore a
proposed target of this class.6 We intend to cross screen our
imidazopyridines against QcrB and results will be reported in due
course.
The in vivo pharmacokinetics (PK) of compounds 13 and 18
were evaluated in male mice by oral (PO) and intravenous (IV)
routes of administration at 3 and 1 mg/kg dosing levels,
respectively (Table 3). The in vitro microsomal stability of
compound 13 was evaluated in various species (rat, mouse, dog,
and human) and a range of metabolism was observed (19.3%
metabolized in rat, 79.9% metabolized in mouse, 41.2%
Table 3. In Vivo Mouse PK Evaluation of Imidazo[1,2-
a]pyridines
PO
PO
t1/2
(h)
PO AUC PO Cmax Tmax
IV clearance
(mL/min/kg) % F
compd (ng h/mL) (ng/mL)
(h)
a
a
b
b
13
18
13
18
411
3 850
181
337
0.25
0.5
5
43.1
35.8
31.1
c
c
ND
1.93
13.2
ND
54 200
11 000
15 600
1 160
2.0
0.5
a
b
13 and 18 at 3 mg/kg PO and 1 mg/kg IV. 13 at 100 mg/kg PO
c
and 18 at 10 mg/kg PO. ND = not determined value because
compound remained after the 24 h time point; extrapolation from raw
data would suggest t1/2 >12 h and clearance would be estimated at
moderate to slow (see the Supporting Information).
C
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ACS Medicinal Chemistry Letters
Letter
Author Contributions
metabolized in dog, and 0% metabolized in human). The lack of
human (microsomal) metabolism observed prompted evaluation
of 13 against a panel of human cytochrome P-450 enzymes. It
was found that compound 13 only inhibited 2.8% of CYP2D6,
11.5% of CYP2C9, and 0% of CYP 3A4 at 10 μM. Thus, 13 is not
an inhibitor of these CYP isoforms. However, compounds 13 and
18 were found to be time dependent inhibitors of human
CYP3A4 at 10 μM, a concentration well above their respective
MICs. Additionally, compounds 13 and 18 were profiled to
identify metabolites in mouse, rat, and human microsomes. The
major metabolites observed for both compounds were
monohydroxylations on the imidazopyridine. The exact site of
hydroxylation could not be determined by the fragmentation
pattern and will need to be determined by additional efforts. As
the mouse microsomal assays predicted, compound 13 displayed
only moderate in vivo mouse PK (Table 3). However, when
compound 13 was re-evaluated at a 100 mg/kg PO dose, the PK
parameters were much more promising as the area under the
curve (AUC) increased nonlinearly from 411 to 54 200 ng h/mL.
Also, as predicted by the rat microsomes, the in vivo rat PK
showed slower clearance (25 mL/min/kg) than that observed in
mouse (43 mL/min/kg) following a 1 mg/kg IV dose, along with
greater exposure with an AUC >2000 ng h/mL at a 3 mg/kg oral
dose (see the Supporting Information). Compound 18 had more
promising mouse PK than compound 13 with an AUC of 3850
ng h/mL (compared to AUC of 411 ng h/mL for 13) and a half-
life greater than 12 h (compared to 5 h for 13), Table 3. When
compound 18 was re-evaluated at 10 mg/kg PO, the AUC
increased roughly linearly from 3850 to 11 000 ng h/mL and the
half-life was determined to be 13.2 h. Additional in vivo ADME
properties for compounds 13 and 18 can be found in the
Supporting Information. The free fractions (fu) for compounds
13 and 18 were measured using an equilibrium dialysis method.12
Compound 13 had 8.9% free drug in vivo while 18 had only 0.4%
free drug. Moreover, the Cmax of unbound drug for compound
13 would be 657 nM (near its MIC) at 100 mg/kg PO dose and
18.6 nM at 10 mg/kg PO dose for compound 18 (>4-fold higher
than its MIC). Given the free unbound fraction and duration of
drug exposure (extrapolated AUC of 15 400 ng h/mL at 10 mg/
kg PO) and a very low MIC (<5 nM) against replicating Mtb for
compound 18, we are seeking to evaluate this compound for
efficacy in an in vivo TB infection model and the results will be
reported in due course.
G.C.M. participated in the design, performed the syntheses,
drafted the manuscript, and facilitated interactions. L.D.M.
participated in the design and coordinated interactions through
Dow AgroSciences. P.A.H. and J.C. (from Eli Lilly and
Company) facilitated microsome and PK assessment. H.B.
(NIH) performed MDR- and XDR-Mtb assays. M.B., T.A., J.O.,
and T.P. conducted MICs against replicating Mtb. J.O. and T.P.
provided scientific input and assisted with the manuscript.
M.J.M. drafted the manuscript and participated in the design and
direction of the project.
Funding
Funding was provided by NIH Grant AI054193, Dow Agro-
Sciences, and NSF Grant CHE-0741793.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was funded, in part, by the Intramural Research
Program of NIAID, NIH. We gratefully acknowledge funding of
the fundamental discovery and development of new anti-TB
agents by Grant 2R01AI054193 from the National Institutes of
Health (NIH) to the Notre Dame group and would like to thank
the Mass Spectrometry and Proteomics Facility (Bill Boggess
and Michelle Joyce), which is supported by the Grant CHE-
0741793 from the NSF. The work at IDRI was funded in part by
Eli Lilly and Company in support of the mission of the Lilly TB
Drug Discovery Initiative. We thank Prof. Jennifer DuBois for
regular scientific discussions. We thank Allen Casey and
Stephanie Florio for technical assistance and Joshua Odingo
for helpful discussion.
ABBREVIATIONS
■
DME, 1,2-dimethoxyethane; EDC, N-(3-dimethylaminoprop-
yl)-N′-ethylcarbodiimide hydrochloride; DMAP, 4-dimethyla-
minopyridine; HCl, hydrochloric acid; ADME, absorption
distribution metabolism and excretion
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ASSOCIATED CONTENT
■
S
* Supporting Information
Full experimental details for compounds synthesized, descrip-
tions of assays, PK data, as well as copies of relevant NMR
spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Phone: +1 574-631-7571. Fax: +1 574-631-6652. E-mail:
mmiller1@nd.edu.
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