Discovery of Potent Selective Nonzinc Binding Autotaxin Inhibitor BIO-32546

Article abstract of DOI:10.1021/acsmedchemlett.1c00211

Autotaxin (ATX) is a lysophospholipase D that is the main enzyme responsible for generating LPA in body fluids. Although ATX was isolated from a conditioned medium of melanoma cells, later it was discovered to play a critical role in vascular and neuronal development. ATX has also been implicated in primary brain tumor, fibrosis, and rheumatoid arthritis, as well as neurological diseases such as multiple sclerosis, Alzheimer's disease, and neuropathic pain. As ATX and LPA levels are increased upon neuronal injury, a selective ATX inhibitor could provide a new approach to treat neuropathic pain. Herein we describe the discovery of a novel series of nonzinc binding reversible ATX inhibitors, particularly a potent, selective, orally bioavailable, brain-penetrable tool compound BIO-32546, as well as its synthesis, X-ray cocrystal structure, pharmacokinetics, and in vivo efficacy.

Full text of DOI:10.1021/acsmedchemlett.1c00211

pubs.acs.org/acsmedchemlett
Letter
Discovery of Potent Selective Nonzinc Binding Autotaxin Inhibitor
BIO-32546
Bin Ma,* Lei Zhang, Lihong Sun, Zhili Xin, Gnanasambandam Kumaravel, Douglas Marcotte,
Jayanth V. Chodaparambil, Qin Wang, Angela Wehr, Jing Jing, Victor Sukbong Hong, Ti Wang,
Carol Huang, Zhaohui Shao, and Sha Mi
Cite This: ACS Med. Chem. Lett. 2021, 12, 1124−1129
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Autotaxin (ATX) is a lysophospholipase D that is
the main enzyme responsible for generating LPA in body fluids.
Although ATX was isolated from a conditioned medium of
melanoma cells, later it was discovered to play a critical role in
vascular and neuronal development. ATX has also been implicated
in primary brain tumor, fibrosis, and rheumatoid arthritis, as well as
neurological diseases such as multiple sclerosis, Alzheimer’s
disease, and neuropathic pain. As ATX and LPA levels are
increased upon neuronal injury, a selective ATX inhibitor could
provide a new approach to treat neuropathic pain. Herein we describe the discovery of a novel series of nonzinc binding reversible
ATX inhibitors, particularly a potent, selective, orally bioavailable, brain-penetrable tool compound BIO-32546, as well as its
synthesis, X-ray cocrystal structure, pharmacokinetics, and in vivo efficacy.
KEYWORDS: ATX, LPC, LPA, inhibitor, selectivity, brain-penetration
a
Scheme 1. Synthesis of Compound 6
utotaxin (ATX or ENPP2) is an extracellular enzyme
Awhich is one of the seven members of the ecto-nucleotide
Figure 1. Chemical structures of LPA 14:0 (1), HA-155 (2), Lilly’s
ATXi (3), and GLPG1690 (4).
a
Reagents and conditions: (a) i. MsCl, NEt3, CH2Cl2, rt, 99%; ii. 7-
bromonaphthalen-2-ol, Cs2CO3, DMF, 80 °C, 55%; (b) i. NIS, ZrCl4,
CH2Cl2, reflux, 94%; ii. FSO2CF2CO2Me, CuI, HMPA, DMF, 80 °C,
98.5%; (c) BuLi, DMF, THF, −78 °C, 97.3%; (d) MeMgBr, THF, 0
°C, 92.6%; (e) MsCl, DIPEA, CH2Cl2, rt; (f) Cs2CO3, DMF, 80 °C;
(g) LiOH, THF, rt, (34.2% combined from e−g); (h) SFC
separation, 30%.
Figure 2. Chemical structures of hit 5 and BIO-32546 (6).
pyrophosphatase/phosphodiesterase family with structurally
related catalytic domains.1 Originally isolated from a
conditioned medium of melanoma cells in 1992,2 ATX was
discovered to play a major role in the development of vascular3
and nervous4 systems and malignancy.5 Its enzymatic activity
remained to be an enigma until it was shown to be identical to
Received: April 12, 2021
Accepted: June 10, 2021
Published: June 14, 2021
https://doi.org/10.1021/acsmedchemlett.1c00211
© 2021 American Chemical Society
ACS Med. Chem. Lett. 2021, 12, 1124−1129
1124

ACS Medicinal Chemistry Letters
pubs.acs.org/acsmedchemlett
Letter
glycoprotein lysophospholipase D (lysoPLD) in 2002.6 ATX is
the main enzyme responsible for generating lysophosphatidic
acid (LPA) in body fluids by catalyzing the hydrolysis of
lysophosphatidylcholine (LPC) to LPA and choline.7
LPA is a bioactive phospholipid with diverse functions in
almost every mammalian cell line.8 LPA signals through six
distinct G-protein-coupled receptors (i.e., LPA1−6), leading to
various cellular responses including the stimulation of cell
migration, proliferation, and survival. The ATX−LPA signaling
pathway is implicated in a variety of human pathologies
including angiogenesis,9 autoimmune diseases,10 cancer,11
fibrotic diseases,12 inflammation,13 neurodegeneration,14 and
neuropathic pain,15 among others.
Figure 3. Single-crystal X-ray structure of compound 6-HCl salt.
Table 1. SAR on R1 and R2 Positions
a
b
Human ATX FRET assay with FS-3 as substrate (mean, n ≥ 2). Chantest fastpatch.
1125
https://doi.org/10.1021/acsmedchemlett.1c00211
ACS Med. Chem. Lett. 2021, 12, 1124−1129

ACS Medicinal Chemistry Letters
pubs.acs.org/acsmedchemlett
Letter
identified a hit compound 5 (Figure 2), a phosphonic acid-
based inhibitor that inhibits ATX in the FRET assay with good
potency (IC50 = 28 nM). Extensive optimization guided by
structural-based rational design led to the discovery of a
potent, selective, orally bioavailable, brain-penetrable tool
compound BIO-32546 (6, IC50 = 1 nM), a novel nonzinc
binding reversible ATX inhibitor. Herein we describe the
synthesis, structure activity relationship, as well as X-ray
cocrystal structure, pharmacokinetics, and in vivo efficacy.
The preparation of this series of compounds was exemplified
with the synthesis of compound 6 as depicted in Scheme 1.
Mesylation of alcohol 7 followed by phenol displacement led
to ether 8, which was iodinated and converted further to the
CF3 intermediate 9. Transmetalation of the bromide followed
by quenching with DMF gave aldehyde 10, which was
methylated to yield secondary alcohol 11 with good yield.
Sequential mesylation, followed by amine displacement and
ester hydrolysis gave the racemate 14, which was eventually
separated under chiral SFC conditions to give compound 6
and its enantiomer. A single crystal X-ray of compound 6
(Figure 3) was obtained as an HCl salt which unambiguously
established the absolute configuration. Its analogues were all
prepared in a similar way.
As our initial hit 5 is a phosphonic acid, which typically lacks
good oral bioavailability,27 our first move was replacing the
phosphonic acid with a carboxylic acid with the aim to reduce
the polar surface area (tPSA = 96 for 5 and 76 for 15). A
significant drop in potency was observed with compound 15
(IC50 = 3700 nM). Switching to amino acid 16 (IC50 = 1300
nM) further lowered tPSA to 59 and showed a modest
improvement on potency. Encouraged by this result, different
amino acid linkers were screened, and eventually we found that
the restricted amino acid 17 showed reasonable activity (IC50
= 370 nM) with a low tPSA of 50 and cLogP of 3.43. Tackling
the whole head moiety turned out to be quite fruitful as
depicted in Table 1. Replacing the piperidine in compound 17
with a more steric hindered azabicyclo[3.3.1]nonane and
replacing the tail CF3 with CH3 further improved the potency
(18, IC50 = 38 nM), while maintaining the molecular weight
below 500.28 Switching the regiosubstitution from 6- to 7- led
to a potency breakthrough to the single digit nm range with
compound 19 (IC50 = 8.2 nM).
At this stage, we began to profile this series of compounds,
and immediately we noticed that 17−19 all showed more than
50% hERG inhibition at 10 μM. The slightly less lipophilic
analogue 20 showed somewhat improved hERG mitigation
compared with 19 (65% vs 84% @ 10 μM). Eventually, α-
methylation on the benzyl amine position satisfied the hERG
issue with compound 21 showed 24.4% inhibition at 10 μM
with slightly improved potency (IC50 = 3.6 nM). We were
delighted to see that α-methylated azabicyclo[3.2.1]octane
Figure 4. (A). X-ray cocrystal structure of compound 6 (PDB:
7MFH) with mATX (Cyan: 6, Yellow: LPA 14:0, overlay from PDB:
3NKN18). (B). Overlay of 6 (Yellow) with GLPG1690 (Magentas,
PDB: 5MHP22).
Targeting the ATX-LPA signaling pathway for therapeutic
potential has gained increasing interest from both academic
and industrial settings and been reviewed extensively.16,17 Both
lipid-like and nonlipid ATX inhibitors have been discovered,
with X-ray cocrystal structures disclosed for zinc binder LPA
(14:0, 1)18 itself, and HA-155 (2).19 Nonacid potent inhibitors
like 3 (ATX IC50 = 2.2 nM)20 are emerging, and so far, only
one ATX inhibitor GLPG1690 (4, ATX IC50 = 131 nM) has
moved to clinic trials directed toward idiopathic pulmonary
fibrosis (IPF) (Figure 1),21,22 but it has stopped at phase 3
trials recently. Given the increasing interest of targeting ATX
for neurology indications, a brain-penetrable, orally bioavail-
able ATX inhibitor is desirable but has yet to be reported.
Encouraged by the evidence that ATX and LPA levels are
increased upon neuronal injury and that production of LPA
up-regulates pain-related proteins through the LPA1 recep-
tor,23 we were particularly interested in developing an ATX
inhibitor for neuropathic pain. Very recently, it was reported
that an ATX inhibitor ONO-8430506 could ameliorate
neuropathic pain symptom in CD rat model at 30 mg/
kg,24,25 which further strengthens this hypothesis. Our initial
screening of an internal lipid mimetic chemical library derived
from our previous S1P work26 and subsequent optimization
a
Table 2. Single-Dose Pharmacokinetic Parameters of 6 in Rats, Dogs, and Cynomolgus Monkeys
species
rat
route
dose (mg/kg)
Clp (mL/min/kg)
29
Vss (L/kg)
3.0 0.3
t1/2 (hr)
AUC0−24 h (ng/mL*hr)
Cmax (ng/mL)
Tmax (hr)
F (%)
b
IV
1
10
0.2
1
0.2
1
4
3
0.4
594 98
3969 235
1390 138
6591 455
369 54
bc
,
PO
IV
813 144
376 19
1.6 0.4
66
69
34
b
dog
1.7 0.3
9.3 1.3
2.0 0.2
2.4 0.2
14
4
2
b
PO
2
4
1
1
b
monkey
IV
0.1
b
PO
614 110
89
4
a
b
c
Mean SD (n = 3). Formulation IV, and PO, solution in 15%HPCD. Brain/plasma ratio at 4 h = 0.2.
1126
https://doi.org/10.1021/acsmedchemlett.1c00211
ACS Med. Chem. Lett. 2021, 12, 1124−1129

ACS Medicinal Chemistry Letters
pubs.acs.org/acsmedchemlett
Letter
a
Table 3. Single-Dose Plasma and Brain Pharmacokinetic Parameters of 6 in mice.
route
dose (mg/kg)
2.32
tissue
Cl (mL/min/kg)
6.09
Vss (L/kg)
2.36
t1/2 (hr)
AUC0−24 h (ng/mL*hr)
Cmax (ng/mL)
Tmax (hr)
F (%)
b
IV
plasma
brain
plasma
brain
4.72
6170
3020
12200
1270
274
1070
823
3.00
3.00
7.00
bc
,
PO
10
51
8840
a
b
c
In male C57BL/6 mice (n = 3). Formulation IV, and PO, solution in 15%HPCD. Kp,uu = 0.11.
6), coincidental with the original hit, affording a moderate
blocking effect with lowered clearance (CL = 29 mL/min/kg)
in rat PK, while maintaining good ATX potency (IC50 = 1.0
0.5 nM, N = 5) and low human microsomal clearance (CL =
7.6 mL/min/kg). Compound 6 maintained low hERG
inhibition (21.3% @ 10 μM) and excellent selectivity over
receptors S1P1−5 and LPA1−3,5 (IC50 > 10 μM).
Compound 6 was cocrystallized with mouse ATX, and the
X-ray structure was solved at 2.3 Å. As shown in Figure 4A, the
tail of compound 6 binds to the hydrophobic pocket and the
bicyclic head portion binds to the hydrophobic channel with
hydrogen bond between carboxylate and His251. Unlike LPA,
compound 6 does not bind to the zinc ion,18 but shares a
similar binding mode with GLPG1690 (Figure 4B).22
Compound 6 exhibits good solubility (73.2 μg/mL at pH 7),
good permeability (Papp (A-B/B-A) 16.8/40.3 × 10−6 cm/s in
CACO-2 cell). It has an ELogD of 4.73 at pH 7.4. It showed
improved plasma protein binding (0.45% and 0.66% free
fraction in rat and human, respectively) compared with its
methyl tail analogue 23. Its IC50s at CYP isoforms (3A4, 1A2,
2C19, 2C9, 2D6) were all greater than 10 μM, and its hERG
IC50 is greater than 10 μM. Compound 6 is negative in in vitro
GSH trapping studies.
Figure 5. (A). Efficacy in rat CFA model with single doses of 6 at 0.1,
0.3, 3, and 10 mg/kg. (B). LPA 20:4 reduction and drug
concentration at 6 h after oral dosing of 6.
Furthermore, compound 6 shows good pharmacokinetics
across species as depicted in Table 2. In rat, it has a half-life of
3 h with plasma AUC of 594 ng/mL*hr after IV dosing of 1
mg/kg. It shows good oral bioavailability (F = 66%) with total
brain/plasma ratio = 0.2 at 4 h with 97 ng/mL brain
concentration after oral dosing at 10 mg/kg. Compound 6 also
demonstrated good pharmacokinetics in mice with a low
clearance and good bioavailability (F = 51%) (Table 3). Its
mice brain protein binding is slightly higher than plasma
(0.599% free fraction in plasma and 0.096% free fraction in
brain), similar to rat (0.45% in plasma vs 0.12% in brain). The
total brain exposure is 8840 ng/mL after oral dosing at 10 mg/
kg to mice, and the corresponding unbound Cmax in brain is 1.5
nM, well above ATX IC50 (1.0 nM). It was speculated that the
brain penetrability of those zwitterionic compounds is likely
transporter-mediated; however, no proof was obtained yet.
Compound 6 demonstrated significant LPA reduction (IC50
= 53 26 nM, N = 5) in a human plasma LPA assay (Figure
S1). A similar LPA reduction (IC50 = 47 20 nM, N = 4) was
observed in a rat plasma LPA assay. Supported by this data, we
then tested compound 6 in rat CFA model, an acute pain
model.30 As shown in Figure 5A, compound 6 demonstrated
dose-dependent efficacies with sign of effect as low as 0.3 mg/
kg, and sustained effect for 24 h with 3 mg/kg and 10 mg/kg
oral dose once. Dose dependent LPA reduction was also
observed (Figure 5B). Remarkably, LPA level was reduced to
48% and 61% in plasma at 6 h after oral dosing at 10 mg/kg
and 3 mg/kg, respectively. It should be noted that since Tmax of
compound 6 in rat was 2 h and maximal LPA reduction was
observed at 2 h based on a 3 mg/kg rat PK/PD correlation
study (Figure S2), the maximal efficacy observed at 6 h time
(compound 23) not only addressed the hERG problem (21.9%
@ 10 μM) but also improved the potency significantly (IC50
=
1.4 nM). Interestingly, the other enantiomers 22 and 24
showed much reduced potency, together with abrogated hERG
activity. All 4 compounds (21-24) demonstrated excellent
selectivity over receptors S1P1−5 and LPA1−3, 5 with IC50
more than 10 μM.
Compound 23 was further profiled and showed reasonable
solubility (27 μg/mL at pH 7), good permeability (Papp (A-B/
B-A) 6.29/14.47 × 10−6 cm/s in CACO-2 cell), and high
plasma protein binding (0.22% and 0.18% free fraction in rat
and human, respectively) and negative in in vitro GSH
trapping studies. However, it showed high in vitro clearance in
rat liver microsomes (equivalent of 73% hepatic blood flow),
though low in human hepatocytes (12%). The in vivo PK in rat
confirmed its high systemic clearance (CL = 94 mL/min/kg),
but it showed 0.8 total brain/plasma ratio at 4 h with 103 ng/
mL brain concentration after oral dosing at 10 mg/kg.
Encouraged by this result, we looked at the metabolic profile
of compound 23. Metabolite identification (MetID) in rat and
human liver microsomes and hepatocytes identified mono-
oxygenation as a major pathway and predominantly on the
substituted cyclohexane. Acyl-glucuronidation was identified as
a minor pathway, and no oxidation on the naphthalene ring
and bicyclic group was observed. This directed our focus to
improving the metabolic stability of the cyclohexyl ring, which
led to the identification of the CF3 substitution29 (compound
1127
https://doi.org/10.1021/acsmedchemlett.1c00211
ACS Med. Chem. Lett. 2021, 12, 1124−1129

ACS Medicinal Chemistry Letters
pubs.acs.org/acsmedchemlett
Letter
point for 3 mg/kg dose with LPA level recovered back to 61%
implies that a sustained LPA reduction might be required. The
unbound LPA EC50 (1.1 nM) was also consistent with ATX
IC50 (1.0 nM).
Sha Mi − Neurology, Biogen Inc., Cambridge, Massachusetts
02142, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acsmedchemlett.1c00211
In summary, we have discovered a novel series of nonzinc
binding ATX inhibitors starting from a phosphonic acid hit.
The hERG liability was successfully mitigated by introduction
of a methyl group to the benzylic position. A potent, selective,
orally bioavailable, brain-penetrable tool compound BIO-
32546 has been identified and has demonstrated in vivo
efficacy in a model of acute pain with good PK/PD correlation.
Further profiling of the compound in other neurological
disease models will be disclosed in due course.
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Bioassay group for the support on
compound screening, DMPK group for the support on
compound profiling and PK studies, and neuropharmacology
group for the support on the in vivo studies. The authors thank
Ying Liu for collecting HRMS data. The authors thank Dr.
Richard Staples for collecting the single crystal X-ray data. The
authors thank Dr. Brian Lucas for critically reading the
manuscript.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acsmedchemlett.1c00211.
■
sı
Experimental details for synthetic procedures and
analytical data for key compounds and assay conditions,
crystallographic data for compound 6 (PDF)
Accession Codes
ABBREVIATIONS
■
Structure data associated with this study have been deposited
to the RCSB Protein Data Bank (http://www.rcsb.org) and
can be accessed with the following codes: mATX bound to 6 is
7MFH. Authors will release the atomic coordinates and
experimental data upon article publication.
CL, clearance; GSH, glutathione; HPCD, hydroxypropyl-beta-
cyclodextrin; IV, intravenous; PK, pharmacokinetics; PO, oral;
S1P, sphingosine 1-phosphate; SAR, structure activity relation-
ship; SFC, supercritical fluid chromatography
REFERENCES
AUTHOR INFORMATION
Corresponding Author
Bin Ma − Medicinal Chemistry, Biogen Inc., Cambridge,
Massachusetts 02142, United States; orcid.org/0000-
0002-3913-0545; Phone: 617 914-4955; Email: bin.ma@
biogen.com
■
■
(1) Stefan, C.; Jansen, S.; Bollen, M. NPP-type ectophosphodies-
terases: unity in diversity. Trends Biochem. Sci. 2005, 30, 542−550.
(2) Stracke, M. L.; Krutzsch, H. C.; Unsworth, E. J.; Arestad, A.;
Cioce, V.; Schiffmann, E.; Liotta, L. A. Identification, purification, and
partial sequence analysis of autotaxin, a novel motility-stimulating
protein. J. Biol. Chem. 1992, 267, 2524−2529.
(3) van Meeteren, L. A.; Ruurs, P.; Stortelers, C.; Bouwman, P.; van
Rooijen, M. A.; Pradere, J. P.; Pettit, T. R.; Wakelam, M. J.; Saulnier-
Blache, J. S.; Mummery, C. L.; Moolenaar, W. H.; Jonkers, J.
Autotaxin, a secreted lysophospholipase D, is essential for blood vessel
formation during development. Mol. Cell. Biol. 2006, 26, 5015−5022.
(4) Fotopoulou, S.; Oikonomou, N.; Grigorieva, E.; Nikitopoulou,
I.; Paparountas, T.; Thanassopoulou, A.; Zhao, Z.; Xu, Y.;
Kontoyiannis, D. L.; Remboutsika, E.; Aidinis, V. ATX expression
and LPA signalling are vital for the development of the nervous
system. Dev. Biol. 2010, 339, 451−461.
Authors
Lei Zhang − Medicinal Chemistry, Biogen Inc., Cambridge,
Massachusetts 02142, United States
Lihong Sun − Medicinal Chemistry, Biogen Inc., Cambridge,
Massachusetts 02142, United States
Zhili Xin − Medicinal Chemistry, Biogen Inc., Cambridge,
Massachusetts 02142, United States
Gnanasambandam Kumaravel − Medicinal Chemistry,
Biogen Inc., Cambridge, Massachusetts 02142, United States
Douglas Marcotte − Physical Biochemistry, Biogen Inc.,
Cambridge, Massachusetts 02142, United States
Jayanth V. Chodaparambil − Physical Biochemistry, Biogen
Inc., Cambridge, Massachusetts 02142, United States
Qin Wang − Drug Metabolism & Pharmacokinetics, Biogen
Inc., Cambridge, Massachusetts 02142, United States
Angela Wehr − Drug Metabolism & Pharmacokinetics, Biogen
Inc., Cambridge, Massachusetts 02142, United States
Jing Jing − Drug Metabolism & Pharmacokinetics, Biogen Inc.,
Cambridge, Massachusetts 02142, United States
Victor Sukbong Hong − Discovery Bioassay, Biogen Inc.,
Cambridge, Massachusetts 02142, United States
Ti Wang − Discovery Bioassay, Biogen Inc., Cambridge,
Massachusetts 02142, United States
(5) Liu, S.; Murph, M.; Panupinthu, N.; Mills, G. B. ATX-LPA
receptor axis in inflammation and cancer. Cell Cycle 2009, 8, 3695−
3701.
(6) Tokumura, A.; Majima, E.; Kariya, Y.; Tominaga, K.; Kogure, K.;
Yasuda, K.; Fukuzawa, K. Identification of human plasma
lysophospholipase D, a lysophosphatidic acid-producing enzyme, as
autotaxin, a multifunctional phosphodiesterase. J. Biol. Chem. 2002,
277, 39436−39442.
(7) Umezu-Goto, M.; Kishi, Y.; Taira, A.; Hama, K.; Dohmae, N.;
Takio, K.; Yamori, T.; Mills, G. B.; Inoue, K.; Aoki, J.; Arai, H.
Autotaxin has lysophospholipase D activity leading to tumor cell
growth and motility by lysophosphatidic acid production. J. Cell Biol.
2002, 158, 227−233.
(8) Moolenaar, W. H.; van Meeteren, L. A.; Giepmans, B. N. The ins
and outs of lysophosphatidic acid signaling. BioEssays 2004, 26, 870−
881.
Carol Huang − Neurology, Biogen Inc., Cambridge,
Massachusetts 02142, United States
Zhaohui Shao − Neurology, Biogen Inc., Cambridge,
Massachusetts 02142, United States
(9) Rivera-Lopez, C.; Tucker, A.; Lynch, K. Lysophosphatidic acid
(LPA) and angiogenesis. Angiogenesis 2008, 11, 301−310.
(10) Bourgion, S. G.; Zhao, C. Autotaxin and lysophospholipids in
rheumatoid arthritus. Curr. Opin. Invest. Drugs 2010, 11, 515−526.
1128
https://doi.org/10.1021/acsmedchemlett.1c00211
ACS Med. Chem. Lett. 2021, 12, 1124−1129

ACS Medicinal Chemistry Letters
pubs.acs.org/acsmedchemlett
Letter
(11) Willier, S.; Butt, E.; Grunewald, T. G. P. Lysophosphatidic acid
(LPA) signalling in cell migration and cancer invasion: A focused
review and analysis of LPA receptor gene expression on the basis of
more than 1700 cancer microarrays. Biol. Cell 2013, 105, 317−333.
(12) Tager, A. M.; LaCamera, P.; Shea, B. S.; Campanella, G. S.;
Selman, M.; Zhao, Z.; Polosukhin, V.; Wain, J.; Karimi-Shah, B. A.;
Kim, N. D.; Hart, W. K.; Pardo, A.; Blackwell, T. S.; Xu, Y.; Chun, J.;
Luster, A. D. The lysophosphatidic acid receptor LPA1 links
pulmonary fibrosis to lung injury by mediating fibroblast recruitment
and vascular leak. Nat. Med. 2008, 14, 45−54.
enhances the antitumor effect of Paclitaxel in a breast cancer model.
ACS Med. Chem. Lett. 2020, 11, 1335−1341.
(26) Ma, B.; Guckian, K. M.; Lin, E. Y.-S.; Lee, W.-C.; Scott, D.;
Kumaravel, G.; Macdonald, T. L.; Lynch, K. R.; Black, C.; Chollate,
S.; Hahm, K.; Hetu, G.; Jin, P.; Luo, Y.; Rohde, E.; Rossomando, A.;
Scannevin, R.; Wang, J.; Yang, C. Stereochemistry activity relationship
of orally active tetralin S1P agonist prodrugs. Bioorg. Med. Chem. Lett.
2010, 20, 2264−2269.
(27) He, G.-X.; Krise, J. P.; Oliyai, R. Prodrugs of Phosphonates,
Phosphinates, and Phosphates. In Prodrugs: Challenges and Rewards;
Stella, V., Borchardt, R., Hageman, M., Oliyai, R., Maag, H., Tilley, J.,
Eds.; Springer Science & Business Media; 2007; pp 225−263.
(28) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J.
Experimental and computational approaches to estimate solubility and
permeability in drug discovery and development settings. Adv. Drug
Delivery Rev. 2001, 46 (1−3), 3−26.
(29) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.;
Meanwell, N. A. Applications of fluorine in medicinal chemistry. J.
Med. Chem. 2015, 58, 8315−8359.
(30) Gould, H. J., III Complete Freund’s adjuvant-induced
hyperalgesia: a human perception. Pain 2000, 85, 301−303. and
references in ref 30.
(13) Zhao, Y.; Natarajan, V. Lysophosphatidic acid (LPA) and its
receptors: Role in airway inflammation and remodeling. Biochim.
Biophys. Acta, Mol. Cell Biol. Lipids 2013, 1831, 86−92.
(14) Chun, J. Lysophospholipid Receptors Signalling and Biochemistry;
John Wiley & Sons Inc, 2013; p 813.
(15) Inoue, M.; Rashid, M. H.; Fujita, R.; Contos, J. J. A.; Chun, J.;
Ueda, H. Initiation of neuropathic pain requires lysophosphatidic acid
receptor signaling. Nat. Med. 2004, 10, 712−714.
(16) Castagna, D.; Budd, D. C.; Macdonald, S. J. F.; Jamieson, C.;
Watson, A. J. B. Development of autotaxin inhibitors: An overview of
the patent and primary literature. J. Med. Chem. 2016, 59, 5604−5621.
(17) Nikolaou, A.; Kokotou, M. G.; Limnios, D.; Psarra, A.;
Kokotos, G. Autotaxin inhibitors: a patent review (2012−2016).
Expert Opin. Ther. Pat. 2017, 27, 815−829.
(18) Nishimasu, H.; Okudaira, S.; Hama, K.; Mihara, E.; Dohmae,
N.; Inoue, A.; Ishitani, R.; Takagi, J.; Aoki, J.; Nureki, O. Crystal
structure of autotaxin and insight into GPCR activation by lipid
mediators. Nat. Struct. Mol. Biol. 2011, 18, 205−213.
(19) Albers, H. M. H. G.; Hendrickx, L. J. D.; van Tol, R. J. P.;
Hausmann, J.; Perrakis, A.; Ovaa, H. Structure-based design of novel
boronic acid-based inhibitors of autotaxin. J. Med. Chem. 2011, 54,
4619−4626.
(20) Jones, S. B.; Pfeifer, L. A.; Bleisch, T. J.; Beauchamp, T. J.;
Durbin, J. D.; Klimkowski, V. J.; Hughes, N. E.; Rito, C. J.; Dao, Y.;
Gruber, J. M.; Bui, H.; Chambers, M. G.; Chandrasekhar, S.; Lin, C.;
McCann, D. J.; Mudra, D. R.; Oskins, J. L.; Swearingen, C. A.;
Thirunavukkarasu, K.; Norman, B. H. Novel autotaxin inhibitors for
the treatment of osteoarthritis pain: lead optimization via structure-
based drug design. ACS Med. Chem. Lett. 2016, 7, 857−861.
(21) van der Aar, E.; Fagard, L.; Desrivot, J.; Dupont, S.; Heckmann,
B.; Blanque, R.; Gheyle, L.; Ralic, J.; Vanhoutte, F. Favorable human
safety, pharmacokinetics and pharmacodynamics of the autotaxin
inhibitor GLPG1690, a potential new treatment in COPD. Eur. Respir.
J. 2015, 46, OA484.
(22) Desroy, N.; Housseman, C.; Bock, X.; Joncour, A.; Bienvenu,
A.; Cherel, L.; Labeguere, V.; Rondet, E.; Peixoto, C.; Grassot, J.-M.;
Picolet, O.; Annoot, D.; Triballeau, N.; Monjardet, A.; Wakselman, E.;
Roncoroni, V.; Le Tallec, S.; Blanque, R.; Cottereaux, C.;
Vandervoort, N.; Christophe, T.; Mollat, P.; Lamers, M.; Auberval,
M.; Hrvacic, B.; Ralic, J.; Oste, L.; van der Aar, E.; Brys, R.;
Heckmann, B. Discovery of 2-[[2-ethyl-6-[4-[2-(3-hydroxyazetidin-1-
yl)-2-oxo-ethyl]-piperazin-1-yl]-8-methyl-imidazo[1,2-a]pyridin-3-yl]-
methyl-amino]-4-(4-fluorophenyl)thiazole-5-carbonitrile
(GLPG1690), a first-in-class autotaxin inhibitor undergoing clinical
evaluation for the treatment of idiopathic pulmonary fibrosis. J. Med.
Chem. 2017, 60, 3580−3590.
(23) Inoue, M.; Ma, L.; Aoki, J.; Chun, J.; Ueda, H. Autotaxin, a
synthetic enzyme of lysophosphatidic acid (LPA), mediates the
induction of nerve-injured neuropathic pain. Mol. Pain 2008, 4, 6.
(24) Uranbileg, B.; Ito, N.; Kurano, M.; Kano, K.; Uchida, K.;
Sumitani, M.; Aoki, J.; Yatomi, Y. Inhibition of autotaxin activity
ameliorates neuropathic pain derived from lumbar spinal canal
stenosis. Sci. Rep. 2021, 11 (1), 3984.
(25) Iwaki, Y.; Ohhata, A.; Nakatani, S.; Hisaichi, K.; Okabe, Y.;
Hiramatsu, A.; Watanabe, T.; Yamamoto, S.; Nishiyama, T.;
Kobayashi, J.; Hirooka, Y.; Moriguchi, H.; Maeda, T.; Katoh, M.;
Komichi, Y.; Ota, H.; Matsumura, N.; Okada, M.; Sugiyama, T.; Saga,
H.; Imagawa, A. ONO-8430506: A novel autotaxin inhibitor that
1129
https://doi.org/10.1021/acsmedchemlett.1c00211
ACS Med. Chem. Lett. 2021, 12, 1124−1129