Optimization of ether and aniline based inhibitors of lactate dehydrogenase

Article abstract of DOI:10.1016/j.bmcl.2021.127974

Lactate dehydrogenase (LDH) is a critical enzyme in the glycolytic metabolism pathway that is used by many tumor cells. Inhibitors of LDH may be expected to inhibit the metabolic processes in cancer cells and thus selectively delay or inhibit growth in transformed versus normal cells. We have previously disclosed a pyrazole-based series of potent LDH inhibitors with long residence times on the enzyme. Here, we report the elaboration of a new subseries of LDH inhibitors based on those leads. These new compounds potently inhibit both LDHA and LDHB enzymes, and inhibit lactate production in cancer cell lines.

Full text of DOI:10.1016/j.bmcl.2021.127974

Bioorg. Med. Chem. Lett. 41 (2021) 127974
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Optimization of ether and aniline based inhibitors of lactate dehydrogenase
Plamen P. Christova, Kwangho Kima, Somnath Janaa, Ian M. Romainea, Ganesha Raib,
Bryan T. Mottb, Alexander A. Allweila, Alexander Lamersa, Kyle R. Brimacombeb,
Daniel J. Urbanb, Tobie D. Leeb, Xin Hub, Christine M. Lukacsc, Douglas R. Daviesc,
Ajit Jadhavb, Matthew D. Hallb, Neal Greenc, William J. Moored, Gordon M. Stottd,
,
*
Andrew J. Flintd, David J. Maloneyb, Gary A. Sulikowskia, Alex G. Watersona
a Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, United States
b National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, United States
c Beryllium Discovery Corp, 7869 Day Rd West, Bainbridge Island, WA 98110, United States
d NExT Program Support, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick,
MD 21702, United States
A R T I C L E I N F O
A B S T R A C T
Keywords:
Lactate dehydrogenase (LDH) is a critical enzyme in the glycolytic metabolism pathway that is used by many
tumor cells. Inhibitors of LDH may be expected to inhibit the metabolic processes in cancer cells and thus
selectively delay or inhibit growth in transformed versus normal cells. We have previously disclosed a pyrazole-
based series of potent LDH inhibitors with long residence times on the enzyme. Here, we report the elaboration of
a new subseries of LDH inhibitors based on those leads. These new compounds potently inhibit both LDHA and
LDHB enzymes, and inhibit lactate production in cancer cell lines.
Medicinal chemistry
LDH inhibitor
Structure activity relationships
Cancer metabolism
The well-known “Warburg effect” is based on the observation that
the metabolic processes of cancer cells are quite distinct relative to that
of untransformed tissues.1 Indeed, cancer cells tend to rely not upon
mitochondrial oxidative phosphorylation, but instead on comparatively
inefficient, non-oxidative glycolysis-based energy production.2 Glyco-
lytic metabolism hinges upon the production of lactate from pyruvate,
via the lactate dehydrogenase enzymes LDHA and LDHB, either of which
can be overexpressed in cancers.3,4
pyrazole (blue oval, Fig. 1).
Analysis of crystal structures of our reported compounds bound to
Supporting the hypothesis that inhibition of LDH function might
selectively affect the growth of cancer cells due to this altered meta-
bolism, several reports have demonstrated that ablation of LDHA ac-
tivity can affect cancer cell growth in vitro and in vivo.5–9 These reports of
biological validation have been accompanied by reports of a number of
compounds aimed at the inhibition of LDH function.6,10–14 We have
previously described a series of pyrazole-based inhibitors of LDH.15
While these compounds display potent inhibition of LDH at the enzy-
matic and cellular levels, as well as show promising ADME attributes, we
have engaged in ongoing Structure Activity Relationship (SAR) studies
to identify improved compounds, primarily via additional diversifica-
tion around the meta substitution of the phenyl ring attached to the
Fig. 1. Previously reported pyrazole-based LDH inhibitors.15,16
* Corresponding author.
E-mail address: a.waterson@vanderbilt.edu (A.G. Waterson).
https://doi.org/10.1016/j.bmcl.2021.127974
Received 27 November 2020; Received in revised form 8 March 2021; Accepted 13 March 2021
Available online 24 March 2021
0960-894X/© 2021 Elsevier Ltd. All rights reserved.

P.P. Christov et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127974
Me
O
Me
O
Me
O
Me
O
a or b
c
R1
R1
OH
O
Br
O
R2
7a
R2 = -H or -F
R2
R2
R2
8
7b
8
R2 = -H or -F
R2 = -H or -F
R2 = -H or -F
O
N
O
O
Me
O
f
N
N
d,
e,
R3
R2
COOEt
N
R3
R4
Br
R4
R2
SO2NH2
S
SO2NH2
R3 = -H or -F
9
NH
10
R
4 = -Br or -OR1
H2N
COOH
N
SO2NH2
R3
S
N
N
h or i, g
For R4 = Br
COOE
N
Fig. 2. X-ray co-crystal structure of 1a bound to LDHA (PDB code 5W8L).15
Oxygen atoms are shown in red, nitrogens in blue. Lipophilic space is high-
lighted by a blue oval. Surface representation of Lys105 omitted for clarity.
R5
N
SO2NH2
R3
S
R2 R5
N
N
13 a-j
COOH
N
human LDHA (Fig. 2) reveals that a considerable amount of hydrophobic
space is available in the binding pocket occupied by the meta phenyl of 1
(blue oval, Fig. 2). This hypothesis is confirmed by the reported SAR that
shows generally superior cellular potency for compounds with sub-
stitutions that fill in this space. We sought to further occupy this pocket
with alternative substitutions, in a quest to further improve compound
potency and/or pharmacokinetic profiles while reducing lipophilicity.
One such SAR campaign is described elsewhere.16 Here, we describe
another exploration that focuses on the incorporation of heteroatoms
such as oxygen and nitrogen at the meta position; these have the sig-
nificant additional advantage of providing a convenient synthetic
handle for elaboration.
SO2NH2
R3
R4
S
R2
N
N
j, g
For R4 = Br
11, E = Et
12 a-p, E = H
g
R5
N
R5
R2
O
14 a-d
Scheme 2. Preparation of 5-methylene cyclopropyl pyrazole analogs. Reagents
and conditions: (a) R1Br, K2CO3, DMF, 100–160 ◦C; b) R1OH, PPh3, di-t-butyl
diazocarboxylate, THF, 0 ◦C. 95%; c) R1B(OH)2, Cu(OAc)2, pyridine, DCM; (d)
MgBr2-OEt2, DCM, DIPEA; e) Cs2CO3, KI, DMSO; (f) pyrrolidine, EtOH, pTSA
90 ◦C; (g) LiOH or NaOH, dioxane, methanol, water; (h) R5NC, PdCl2(Ph3P)2,
CsF, DMSO, water; (i) NH2R5, K3PO4, Pd(P(tBu)3)2, DMA, 53%; (j) HN(R5)2, Mo
(CO)6, Pd(OAc)2, T-BINAP, Cs2CO3, MeCN, toluene.
The basic synthetic routes used to construct these analogs are
depicted in Schemes 1 and 2. For pyrazoles bearing no substitution at the
5-position, we utilized sequential functionalization of a bromopyrazole.
For most analogs, this compound was synthesized by condensation of
hydrazine onto an aldol product of 2, followed by bromination and
installation of the thiazole by SNAr reaction. Deprotection of the methyl
ether to a phenol allowed installation of diversity using straightforward
alkylation procedures. The phenyl sulfonamide was incorporated from
the corresponding pinacol boronate, and saponification of the ester
yielded analogs 6b-g. In some cases (6a, 6h), the corresponding
commercially available acetophenones were carried through the
sequence.
A survey of small functionalities at the 3-ether position (Table 1)
revealed the potential for good LDHA inhibition in this series. Based on
the methoxy-bearing 6a, a wide range of lipophilic substitutions effected
a small improvement in potency of LDHA inhibition. Indeed, good
tolerance is shown for a simple cyclic alkane (6b), several simply
substituted benzyl systems (6c-e), and a phenyl ether (6h). Interestingly,
a 3-pyridinylmethyl substitution (6g) was ~3 fold less potent compared
with a 2-pyridinyl group (6f). Despite generally good enzyme inhibition,
EtO2C
N
HN
N
O
S
Br
N
a, b, c
d, e
N
Br
OMe
OMe
OH
2
3
4
Table 1
Initial survey of ethers at the 3-position.
COOH
N
EtO2C
Cpd
R1
LDHA IC50 (nM)a
MaPaCa2 Lactate IC50 (µM)b
N
SO2NH2
g,
h,
S
S
6a
6b
6c
6d
6e
6f
methyl
90
29
26
21
39
23
77
17
>57
7.7
R1-Br
N
N
N
N
cyclopentylmethyl
3-fluorobenzyl
3-methoxybenzyl
4-methylbenzyl
2-pyridinylmethyl
3-pyridinylmethyl
phenyl
Br
O
6.1
f
SO2NH2
5.4†
7.5†
>57
>57
9.4†
R1
R1
Br
then i
,
O
6g
5
6 a-h
6h
a
Scheme 1. Preparation of 5-H pyrazole analogs. Reagents and conditions: (a)
C2H5OCHO, NaH; (b) hydrazine, ethanol, 92% (two steps); (c) NBS, DMF, 70%;
(d) ethyl 2-bromothiazole-4-carboxylate, K2CO3, DMSO, 73%; (e) BBr3, DCM,
60%; (f) K2CO3, DMF; (g) 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxabor-
olane), PdCl2(dppf), 1,4-dioxane; (h) Pd(PPh3)4, K2CO3, dioxane, water; (i) 1 M
LiOH, THF, methanol.
IC50 values represent the half maximal (50%) inhibitory concentration as
determined in the previously reported assay,15,16 reported as a mean of 3 de-
terminations Coefficient of Variation (CV) ≤ 0.2 unless otherwise noted by†.
b
IC50 values represent the half maximal (50%) inhibition of lactate produc-
tion in the referenced cell line,15,16 reported as a mean of 3 determinations, CV
≤ 0.4 unless otherwise noted by†.
2

P.P. Christov et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127974
these compounds produced only modest inhibition of LDHA activity in
cells, with none of the compounds demonstrating an IC50 for cellular
lactate production of less than 5 µM.
SAR for LDHA inhibition and cellular effects. Reinforcing a trend
observed in our earlier work, the cellular data did not track well with
biochemical inhibition of LDHA. For example, the morpholine analog
13a showed reasonable LDHA inhibition, but poor cellular activity,
perhaps as a result of the polar oxygen atom. Removing this polarity
(13b-f) generated mixed results in enzyme inhibition, but generally
improved cellular IC50 values by ~3–10 fold. The more elaborated spi-
rocyclic azetidine 13g and the aniline 13h displayed inhibition data
within the same range as the initial amines.
We hypothesized that, much like our previously reported com-
pounds, application of the contemporaneously discovered SAR
regarding pyrazole substutitions15 and phenyl sulfonamide fluorina-
tion16 would afford more potent analogs. Thus, we prepared compounds
bearing an alkyl substituent at the 5-position of the pyrazole, using
synthetic routes similar to those reported previously (Scheme 2)15,16
Elaboration of the acetophenones 7a and 7b to the desired ethers 8
proved easier than late-stage functionalization for most analogs. The
derivatized acetophenones were alkylated twice using the previously
described conditions15,16 to give the 1,3-diketones 10, which were
cyclized to the corresponding pyrazoles 11. As reported, the cyclization
produces a separable mixture of regioisomers; the desired isomer was
cleanly saponified to give the ether analogs 12 a-p.
We postulated that an amide bond would create a planar derivative
that might match more closely with the biphenyl and alkynes previously
reported, and thus have superior residence time and cellular activ-
ity.15,16 These analogs were synthesized from a bromide-bearing inter-
mediate 11 (R4 = Br). The amides were installed with either a coupling
of an isocyanate and subsequent hydrolysis and saponification (for
nitrogen-attached amides 13 a-j) or by a molybdenum-mediated car-
bonylative amidation and saponification (to give carbonyl-attached
amides 14 a-d). Ultimately, these analogs also failed to deliver a
noticeable boost to biochemical or cellular activity. Despite certain an-
alogs displaying potent LDHA inhibition, with IC50 values of less than
10 nM (14a, 14d), the amine and amide subseries as a whole was
somewhat inferior in the cellular lactate inhibition assay compared to
the ether subseries.
The activity data with these compounds (Table 2) was generally
improved relative to the compounds in Table 1, with some analogs
generating single digit nanomolar inhibition of the enzyme and sub-
micromolar inhibition of lactate production in MiaPaCa-2 cells. Com-
pounds without the sulfonamide ring fluorine tended toward lower
activity (e.g. 12i). The matched pair 12m vs. 12l demonstrates an
extreme example of this relationship. Interestingly, we found an
imperfect correlation between enzyme and cellular inhibition data. For
example, while the 5–20 nM inhibition data for analogs 12b-g demon-
strates again a wide tolerance for alkyl ether groups in LDH inhibition,
the accompanying lactate data varies in a different pattern. Analogs 12f
and 12g are the most potent of this set in the lactate assay, despite higher
enzyme IC50 values. We selected the benzyl substitution of 12g for
further elaboration (selected compounds shown). Fluoro substitution on
this benzyl (12h) was well tolerated, but replacement with a heterocycle
(12j) diminished activity. We also elected to explore removal of the
methylene with phenyl ethers 12k-p. While enzyme inhibition for this
phenyl ether subseries was generally weaker than with comparators
bearing alkyl substituents, several analogs still showed lactate inhibition
IC50 values near 1 µM.
As we have previously reported15,16, compounds in the pyrazole
chemotype tend to be potent inhibitors of both LDHA and LDHB. A
similar relationship was found in this work, with LDHB IC50 values
typically 2–4 fold better than those for LDHA (Table 4).
As a class, the ether compounds trend toward superior cellular po-
tency compared to amine-based compounds, not only in the MiaPaCa2
lactate production assay, but also in an A673 Ewing’s Sarcoma line
(Table 4). In general, the effects of the compounds on cellular prolifer-
ation showed a similar trend as the lactate production assay, with the
ether compounds demonstrating low micromolar cytotoxicity in the
MiaPaCa2 line. Notably, activity in A673 cells was typically superior to
1a or 1b for some of the ethers, with 12g, 12h, 12j, and 12p showing
submicromolar proliferation IC50 values.
We also evaluated aniline derivatives (13 a-j, Table 3). These analogs
were prepared either from acetophenones similar to 9 (Scheme 2), but
bearing the required amines, or from a later stage palladium-mediated
Buchwald-Hartwig style coupling reaction17 from the corresponding
bromides (11, R4 = Br) that were carried through the synthetic route
(Scheme 2) from the corresponding acetophenone. A selection of small
saturated cyclic analogs 13 a-f were evaluated, showing a rather narrow
We assessed selected compounds for their binding to LDHA by SPR.
Similar to previously reported compounds, some of the ether-based in-
hibitors (e.g. 12b, 12e, 12h, 12j, and 12p) with submicromolar inhi-
bition of lactate production in the MiaPaCa2 cells showed very tight
binding to LDHA and accompanying long residence times, whereas alkyl
amines, such as 13a, and the aniline 13h, characteristically displayed
faster dissociation kinetics, with inferior cellular data to match.
Table 2
Ether analogs (12) bearing the cyclopropylmethyl pyrazole substitution.
Cpd
R2/3
R4
LDHA IC50 (nM)a
MaPaCa2 Lactate IC50 (µM)b
12a
12b
12c
12d
12e
12f
F/H
F/F
F/F
F/F
F/F
H/F
H/F
F/F
F/H
F/F
F/H
H/H
F/F
F/F
F/F
F/F
-O-methyl
8
5.7
-O-(2,2-difluorocyclopropyl)methyl
-O-3-tetrahydrofuranylmethyl
-O-2-tetrahydrofuranylmethyl
-O-cyclopropyl
5
1.4
5
3.0
5
2.9
8
2.1
-O-cyclopentyl
13†
19
22
84
23
34
1060
27
41
71
26
0.71†
0.69
0.67†
3.3†
1.0
12g
12h
12i
-O-benzyl
-O-3-fluorobenzyl
-O-4-fluorobenzyl
12j
-O-(5-(trifluoromethyl)-2-furanyl)methyl
-O-phenyl
12k
12l
1.7
-O-3-fluorophenyl
19
12m
12n
12o
12p
-O-3-fluorophenyl
0.97
1.7
-O-4-fluorophenyl
-O-4-trifluoromethylphenyl
-O-4-methylphenyl
1.1
0.87†
a
IC50 values represent the half maximal (50%) inhibitory concentration as determined in the previously reported assay,15,16 reported as a mean of 3 determinations.
CV ≤ 0.2 unless otherwise noted by†.
b
IC50 values represent the half maximal (50%) inhibition of lactate production in the referenced cell line,15,16 reported as a mean of 3 determinations. CV ≤ 0.33
unless otherwise noted by†.
3

P.P. Christov et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127974
Table 3
Amine (13) and amide (14) analogs.
Cpd
R2/3
R5
LDHA IC50 (nM)a
MaPaCa2 Lactate IC50 (µM)b
13a
13b
13c
13d
13e
13f
H/F
H/F
H/F
H/F
H/F
H/F
F/F
–CH2CH2OCH2CH2–
27
17
47
18
59
15
37
23.4
8.7
–CH2CH2CF2CH2CH2–
–CH2CH2CH(CF3)CH2CH2–
–CH2CF2CH2CH2CH2–
–CH2CH(CF3)CH2CH2CH2–
–CH2CF2CH2CH2–
2.4
8.6
6.9
4.2
13g
24.1†
N
N
13h
13i
H/H
F/F
F/F
F/F
F/F
F/F
F/F
H, phenyl
314
7
6.7
5.0
H, CO-phenyl
–COCH2CH2CH2–
H, -tBu
13j
111
6
6.0†
11.7
19.9†
3.2†
9.1†
14a
14b
14c
14d
–CH2CH2CH2CH2–
–CH2CH2OCH2CH2–
H, benzyl
154†
22
8†
a
IC50 values represent the half maximal (50%) inhibitory concentration as determined in the previously reported assay,15,16 reported as a mean of 3 determinations.
CV ≤ 0.2 unless otherwise noted by†.
b
IC50 values represent the half maximal (50%) inhibition of lactate production in the referenced cell line,15,16 reported as a mean of 3 determinations. CV ≤ 0.33
unless otherwise noted by†.
Table 4
Characterization of selected analogs.
Cpd
LDHB
IC50
MiaPaCa2
Lactate
(µM)b
MiaPaCa2
cytotox
(µM)c
A673
A673
SPR
Rat Microsomal
Stability
PAMPA Perm
(x10ꢀ 6 cm/
sec)
Kinetic
Lactate
cytotox
KD (nM)/
τ
(s)
solubility
(µg/mL)
(µM)a
(µM)b
(µM)c
t
1/2 (min)d
12b
12e
12g
12h
12j
3†
1.4
2.4
5.7
1.4
2.1
2.1
1.1
0.90
1.5
0.008/21,052
0.004/19,230
0.016/88,496
0.91/13,568
0.001/
>30
>30
2.8
4.9
5.8
76.1
>87
72.4
10.7
53.2
3
2.1
1.9
5
0.69
0.67†
1.0
0.59
0.73
1.1
0.42
0.55
0.44
1.1
5
<1
2.9
6†
>30
12.0
100,000
1.1/9,708
0.44/286
1.5/59
12p
13a
13h
13i
19
8†
1
0.87†
23.4
6.7
2.1†
18.7
21.2†
17.4
6.6†
0.55
9.4†
3.1
0.55
20.4
34.5†
5.3
6.2
13.0
1.6
4.4
6.4
5.7
8.7
24.0
>88
49.3
>98
>93
81.0
>30
6.0
2
5.0
2.3
–
>30
>30
14.9
14b
14d
4
19.9†
16.6
>50
–
2
9.1†
15.7
4.7
5.1
–
a
IC50 values represent the half maximal (50%) inhibitory concentration as determined in the previously reported assay,15,16 reported as a mean of 3 determinations.
CV ≤ 0.2 unless otherwise noted by†.
b
IC50 values represent the half maximal (50%) inhibition of lactate,15,16 reported as a mean of 3 determinations. CV ≤ 0.33 unless otherwise noted by†.
c
IC50 values represent the half maximal (50%) inhibition of proliferation,15,16 reported as a mean of 3 determinations. CV ≤ 0.33 unless otherwise noted by†.
d
Assessed using a high-throughput multi-time point stability assay.18
The compounds reported in this manuscript benefited from generally
good solubility and low, but non-limiting, passive permeability char-
acteristics (Table 4). However, the initial assessments of metabolic sta-
bility produced mixed results. Simple alkyl ethers (e.g. 12b, 12e) were
typically reasonable, whereas a benzyl ether (12h) was quite poor, as
was a biphenyl ether (12p). Interestingly, heteroaromatic moieties (12j)
can rescue the stability of the benzyl subseries, indicating promise for
the identification of more stable pseudo-benzylethers. Likewise, selected
amine-based compounds showed some variability in the microsomal
data. While amides in both configurations (13i and 14b) showed good
stability, the introduction of a benzyl position (14d) presented a likely
metabolic soft spot.
Declaration of Competing Interest
The authors declare the following financial interests/personal re-
lationships which may be considered as potential competing interests:
Compounds reported in this manuscript are also exemplified in patent
applications that have been licensed. Under certain circumstances, co-
authors on this manuscript may receive royalties or other payments
through their respective employers.
Acknowledgments
We thank David Myszka at Biosenor Tools for conducting the SPR
experiments. This project has been funded in whole or in part with
federal funds from the National Cancer Institute, National Institutes of
Health, under Contract HHSN261200800001E. The content of this
publication does not necessarily reflect the views or policies of the
Department of Health and Human Services, nor does mention of trade
names, commercial products, or organizations imply endorsement by
the U.S. Government.
This paper presents alternative LDHA inhibitors with heteroatomic
structural elaborations, based on the previously reported pyrazole se-
ries. Selected compounds achieved low nanomolar inhibition of LDHA
and LDHB. However, cellular inhibition of LDH function was less
consistent. From this study, ether analogs bearing a cyclopropylmethyl
pyrazole substitution (scaffold 12) stood out, with some examples
showing single digit picomolar binding affinity for LDHA by SPR and
inhibition of proliferation of an Ewing’s Sarcoma line superior to earlier
leads. Variable SAR with respect to metabolic stability provides a di-
rection for additional optimization of this sub-class of inhibitors.
4

P.P. Christov et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127974
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Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bmcl.2021.127974.
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