Discovery of Irbesartan Derivatives as BLT2 Agonists by Virtual Screening

Article abstract of DOI:10.1021/acsmedchemlett.1c00240

Leuktriene B4 receptor 2 (BLT2) is a G-protein coupled receptor modulation of which is discussed to be a therapeutic option for healing of intestinal lesions. In this work, new BLT2 agonists were identified by a virtual screening of a repurposing library and in vitro assay of the most promising compounds. Irbesartan, an approved type-1 angiotensin II receptor (AT1) antagonist, was identified as a moderate BLT2 agonist. An initial SAR study on the irbesartan scaffold was performed resulting in the discovery of a new potent BLT2 agonist (8f, EC50 = 67.6 nM). Irbesartan and 8f were shown to promote proliferation of epithelial colon cells, an effect which was reversible by a BLT2 antagonist.

Full text of DOI:10.1021/acsmedchemlett.1c00240

pubs.acs.org/acsmedchemlett
Letter
Discovery of Irbesartan Derivatives as BLT2 Agonists by Virtual
Screening
Victor Hernandez-Olmos,∥ Jan Heering,∥ Iris Bischoff-Kont, Alexander Kaps, Rinusha Rajkumar,
̈
Ting Liu, Robert Furst, Dieter Steinhilber, and Ewgenij Proschak*
Cite This: https://doi.org/10.1021/acsmedchemlett.1c00240
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Leuktriene B4 receptor 2 (BLT2) is a G-protein coupled receptor modulation of which is discussed to be a
therapeutic option for healing of intestinal lesions. In this work, new BLT2 agonists were identified by a virtual screening of a
repurposing library and in vitro assay of the most promising compounds. Irbesartan, an approved type-1 angiotensin II receptor
(AT1) antagonist, was identified as a moderate BLT2 agonist. An initial SAR study on the irbesartan scaffold was performed
resulting in the discovery of a new potent BLT2 agonist (8f, EC50 = 67.6 nM). Irbesartan and 8f were shown to promote
proliferation of epithelial colon cells, an effect which was reversible by a BLT2 antagonist.
KEYWORDS: BLT2, Leukotriene B4 receptor type 2, Irbesartan, SAR, Virtual screening
he leukotriene B4 receptor 2 (BLT2), first described in
recently, Matsumoto et al. demonstrated that BLT2 activation
accelerates the healing of intestinal lesions by promoting
epithelial cell proliferation.9 Intestinal lesions are formed in
different pathologies, including inflammatory diseases of the
intestine and cancer, but may also be induced by nonsteroidal
anti-inflammatory drugs (NSAIDs). Thus, BLT2 agonists may
serve as a therapeutic option to heal intestinal lesions.
T
2000 by Yokomizo et al.,1 is primarily known as the low
affinity receptor for leukotriene B4 (LTB4, Figure 1A) in
Our group has recently described the first structure−activity
relationship (SAR) study for a BLT2 agonist based on the
CAY10583 scaffold.10 However, there is still a need to discover
new scaffolds to be used as starting points for the development
of novel potent BLT2 agonists. One of the most convenient
approaches to find new hits is the use of repurposing drug
libraries. The use of this strategy presents some advantages
because it involves the use of well-studied compounds with
potentially lower development costs and shorter development
time.11 The Repurposing Hub Database can be considered as
one of the most complete resources for in silico repurposing
Figure 1. Structures of LTB4 (A), 12-HHT (B), and CAY10583 (C).
contrast to BLT1, which is the high affinity receptor for LTB4.2
Human BLT2 is expressed in a variety of tissues including
spleen, blood leukocytes, liver, ovary, pancreas, heart, prostate
gland, testes, small intestine, kidney, lung, colon, thymus,
muscle, placenta, and skin, where BLT2 is detected in high
concentrations.3 However, studies performed by Okuno et al.
demonstrated that 12(S)-hydroxyheptadeca-5Z,8E,10E-tri-
enoic acid (12-HHT, Figure 1B), which is a byproduct of
thromboxane A2 biosynthesis, can be considered as a potent
endogenous agonist of BLT2.4 BLT2 modulation has been
considered as a potential therapeutic strategy for a variety of
pathologies including diabetic wound healing,5 neuropathic
pain,6 carcinogenesis,7 and inflammatory arthritis.8 Very
Received: April 22, 2021
Accepted: June 25, 2021
© XXXX The Authors. Published by
American Chemical Society
https://doi.org/10.1021/acsmedchemlett.1c00240
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
A

ACS Medicinal Chemistry Letters
pubs.acs.org/acsmedchemlett
Letter
and screening of approved and clinical compounds.12 We
followed a virtual screening approach to identify BLT2 agonists
using the MOE software suite (Chemical Computing Group,
Montreal, Canada). After downloading the database, all
compounds with a molecular weight below 250 Da and
above 650 Da were removed. Furthermore, only compounds
exhibiting an acidic group (indicated by the MOE descriptor
a_acid > 0) were considered for virtual screening. For the
remaining compounds, adjustment of the protonation state
(MOE wash routine) and energy minimization using default
settings were performed. Multiple low energy conformations
were generated using default settings of the LowModeMD
routine, setting the energy window to 5 kJ/mol and the RMSD
cutoff to 0.75 A.
For the generation of the pharmacophore model, three
known active BLT2 agonists CAY10583, 12-(S)-HHT, and
LTB4 were pasted into the MOE database. Subsequently,
adjustment of the protonation state (MOE wash routine) and
energy minimization using default settings was performed. The
initial alignment of the active compounds was performed using
the Pharmacophore Elucidation routine with default settings,
while the conformers were generated during the search by
bond rotation. The top rated superposition was examined
manually and subsequently refined using the Flexible Align-
ment routine. A previous publication on the conformation of
12-(S)-HHT in the receptor bound state by Giusti et al.
demonstrated the importance of the interactions of the
carboxylic group and the −OH group which is supposed to
act as a H-bond acceptor.13 These observations were in perfect
agreement with the SAR of CAY10583, where the removal of
the acidic or the H-bond acceptor group resulted in fully
inactive derivatives. Therefore, we used default settings for
refinement of the existing alignment, while weights for H-Bond
acceptor and carboxylate (O2)-type Centroid were set to 10.
The resulting molecular alignment was used to generate a
pharmacophore model manually, considering the knowledge of
SAR from our previous publication (Figure 2A).10 The
pharmacophore model consisted of six features; the
importance of the anionic group and the H-bond acceptor
group (F4, cyan) was mentioned above, while three hydro-
phobic/aromatic features (F2, F3, F6) as well as a hydrophobic
feature F5 were added.
The pharmacophore search was performed on the prepared
multiconformer database. For this search, a partial match of at
least 5 features was required. Features F1, F4, and F5 were
considered to be essential due to our prior knowledge of the
SAR (vide supra). The pharmacophore search delivered 54
hits, which were inspected manually. The full list of the
potential hits is enclosed in the Supporting Information (SI).
The manual inspection revealed that most of the hits do not
superpose well with the shape of the active ligands, and these
were discarded. The 10 most promising hits were purchased
and tested for their potency in a functional cell-based assay
with detection of accumulation of inositol monophosphate
(IP-1) as a measure for activation of BLT2 (Table 1).
Figure 2. (A) Pharmacophore model based on CAY10583 (purple
sticks), 12-(S)-HHT (pink sticks), and LTB4 (cyan sticks). The
anionic group (F1, red), the H-bond acceptor group (F4, cyan), and
four hydrophobic features (F2, F3, F5, F6) are represented by
spheres. (B) Overlay of irbesartan (orange sticks) and CAY10583
(purple lines) with the pharmacophore model.
the irbesartan scaffold was selected to perform an initial SAR
study.
Most irbesartan derivatives were prepared according to the
synthetic route depicted in Scheme 1.
In the first step of the synthesis, the imidazolone ring was
built in a one-pot procedure by condensation reaction between
the corresponding substituted 2-aminoacetamide (2) and acid
chloride (3) in the presence of triethylamine, followed by
treatment with potassium hydroxide in methanol to give
intermediates 6a−g. In the next step, the amide was
deprotonated with sodium hydride and reacted with benzylic
bromides (5, 6) to yield compounds 7a−g. In the case that R4
is a methyl ester group, hydrolysis of the ester under alkaline
conditions provided the final products 8a−8e. In the case that
R4 is a nitrile group, the final product containing a tetrazole
ring was obtained by reaction of the nitrile precursors (7f,g)
with azidotributyltin (8f,g).
Alternatively, the synthetic routes depicted in Scheme 2
were used to obtain products 13−15. In this case, an
imidazolinidone ring was formed in the first step by reaction
of substituted 2-aminoacetamide (2) and valeraldehyde (9) in
the presence of PTSA. Intermediate 10 can react chemo-
selectively with 5 either through the amino or amide functional
groups. Thus, compound 10a reacted with 5 in the presence of
potassium carbonate in DMF to give tertiary amine 11. On the
contrary, deprotonation of 10b with sodium hydride in DMF
and subsequent nucleophilic attack to 5 gave intermediate 12.
Of the 10 compounds selected, 3 compounds from the
“sartan” family showed BLT2 activation while the other 7 were
inactive. Candesartan and valsartan showed weak activation
with EC50’s around 15−16 μM, while irbesartan (1), which
overlays very nicely with the pharmacophore model and with
the reference agonist CAY10583 (Figure 2B), was confirmed
as a moderate BLT2 activator with EC50 = 410 nM. Therefore,
B
https://doi.org/10.1021/acsmedchemlett.1c00240
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
pubs.acs.org/acsmedchemlett
Letter
a
Table 1. Selected Virtual Screening Hits for BLT2
Activation
Scheme 2
a
Conditions: (a) PTSA, MeOH, reflux, 84%. (b) K2CO3, DMF, 34%.
(c) NaH, DMF, 27%. (d) LiOH, THF/MeOH/H2O, 60 °C, 96%. (e)
nBu3SnN3, p-xylene, 160 °C, 62% for 14 and 6.4% for 15.
a
Scheme 3
compd
BLT2 EC50 SEM (nM)
irbesartan (1)
candesartan
valsartan
azilsartan
setipiprant
elafibranor
DCPIB
zaltoprofen
tienilic acid
chenodeoxycholic acid
410 34
∼15 μM
∼16 μM
inactive
inactive
inactive
inactive
inactive
inactive
inactive
a
Conditions: (a) PTSA, MeOH, reflux, 36−44%. (b) NaH, DMF,
27−32%. (c) nBu3SnN3, p-xylene, 160 °C, 34−39%.
a
Scheme 1
of accumulation of inositol monophosphate (IP-1) as a
measure for activation of BLT2. Efficacy was compared to
that of the reference agonist CAY10583. Compounds were also
tested for off-target activity on BLT1 using the same assay
principle and LTB4 as the reference agonist as a positive
control for BLT1. Irbesartan is a known antagonist for the type
1 angiotensin II (AT1) receptor. Hence, off-target activity on
AT1 was tested in the IP-One assay in antagonist mode in the
presence of the AT1 agonist [Val5]-angiotensin II. The data are
summarized in Table 2.
As in the reference agonist CAY10583, a first series of
irbesartan derivatives was prepared bearing a carboxylic group
instead of tetrazole and different substituents in R3 (8a−e).
Contrary to the SAR observed with CAY10583,15 aromatic
substituents were not well tolerated in this position (8b−d)
and the carboxylic acid brought a significant decrease in
activity (8a E50 = 1490 nM vs 1 EC50 = 410 nM, Table 2).
Variations in the substitution or R1 and R2 were studied next.
Exchange of the original cyclopentyl group for cyclohexyl
brought an increase in activity (8e EC50 = 860 nM vs 8a EC50
= 1490 nM, Table 2). Then, three more examples were
prepared by keeping R1 = CH3 and varying R2. Compound 8f,
with R2 = iPr, resulted in a very active compound with an EC50
= 67.6 nM, while compounds 8g and 15 performed worse than
irbesartan, especially considering maximum efficacy.
a
Conditions: (a) (1) Et3N, DCM; (2) KOH, MeOH, 64−95%. (b)
NaH, DMF, 24−87%. (c) LiOH, THF/MeOH/H2O, 60 °C, 32−
91%. (d) nBu3SnN3, p-xylene, 160 °C, 50−54%.
Hydrolysis of the ester under alkaline conditions provided the
final products. In the case of the hydrolysis of ester 12, also the
elimination product 15 was obtained as a side product, which
was also isolated and tested.
Finally, bicylclic imidazolidinones 19a,b were prepared using
the same route as for compound 14. Chirally pure 2-
aminoacetamides 18a,b were selected as starting materials.
The condensation reaction of 18a,b with valeraldheyde (9)
took place diastereoselectively, providing only one of the
possible diastereoisomers of intermediate 17 in each case
(Scheme 3).
For EC50 determination, the compounds were tested for
their potency in a functional cell-based assay with the detection
Other structural modifications like the substitution inversion
in 13, the imidazolidine ring instead of imidazolone ring as in
C
https://doi.org/10.1021/acsmedchemlett.1c00240
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
pubs.acs.org/acsmedchemlett
Letter
a
Table 2. Activation of Gq Pathway and Cellular Toxicity
BLT2 EC50
SEM (nM)
efficacy rel. to
CAY10583% SEM
AT1 IC50 SEM
live rate (%) after 3 days
compd
R1
R2
R3
R4
(nM)
BLT1
at 50 μM
1
Cyp
Cyp
Cyp
Cyp
Cyp
Cy
nBu
nBu
Ph
tetrazole
COOH
COOH
COOH
COOH
COOH
tetrazole
tetrazole
410 34
1490 168
inactive
6580 956
inactive
69
95
2
3
6
0.6**
inactive
inactive
inactive
inactive
inactive
inactive
inactive
inactive
inactive
inactive
inactive
inactive
inactive
unaffected
92
unaffected
79
unaffected
90
unaffected
56
8a
8b
8c
8d
8e
8f
8g
13
14
15
19a
19b
190 6.6**
>10 μM
8650 620
inactive
155 2.2**
15 1.7**
25 2.1**
7750 660
390 74**
32 8.9**
1010 34**
∼10 μM
Bn
88
inactive
4
CH2CH2Ph
nBu
nBu
860 88
64
42
11
31
36
36
8
4
4
1
4
4
CH3
CH3
iPr
Ph
67.6
4
nBu
550 88
24200 3400
6390 358
8140 815
inactive
unaffected
77
56
89
88
CH3
CH3
nBu
tetrazole
7500 1100
25
2
a
Compounds were tested for activation of BLT2 or BLT1 in the IP-One assay in agonist mode. For BLT2, efficacy was determined by comparison
to reference agonist CAY10583 at 20 μM each. For BLT1, the reference agonist LTB4 served as a positive control. Inhibition of the second off-
target AT1 was tested in the IP-One assay in antagonist mode with [Val5-angiotensin II being present at a constant concentration of 10 nM.
**Indicates that the respective compound is a full agonist with efficacy comparible to irbesartan (1). IP-One assays for the determination of EC50
or IC50 with SEM were conducted at least two times (n = 2). Cellular toxicity was tested on Hep-G2 cells treated for 3 days. ATP content as a
measure for overall metabolic activity and cell survival was determined using the CellTiter-Glo assay. For 50 μM of compound, the live rate is
reported as percent of DMSO control.
14, or the fused rings in 19a,b were not well tolerated and
resulted in weakly active or inactive compounds (Table 2).
Compounds were also tested for activity as AT1 inhibitors.
Most of the irbesartan derivatives, which displayed BLT2
activity, were also potent as AT1 antagonists (Table 2). Several
structural features correlate with both BLT2 and AT1 activity,
suggesting similar binding site properties of these receptors.
Kim et al. described a binding mode of the reference agonist
CAY10583 in the binding site of BLT2 built by homology
modeling.14 It shows an interaction of the carboxylate with
Figure 3. SAR summary of the irbesartan scaffold for BLT2 activation.
Arg301. Arg301 resembles Arg167 in AT1, which interacts
with the tetrazole moiety of the AT1 antagonist olmesartan as
described by Zhang et al.15 Furthermore, Tyr129 in BLT1 is
Ly255283 (1 μM). As depicted in Figure 4, we demonstrated
that the compound 8f similarly to CAY10583 and irbesartan
significantly induced colon epithelial cell proliferation. Of note,
at 0.03 μM, this effect was stronger in 8f-treated cells
compared to cells that were exposed to 0.03 μM irbesartan
or the BLT2 agonist CAY10583. Importantly, BLT2 agonist-
supposed to interact with the carbonyl moiety and is also
present in AT1 as Tyr35, which exhibits a H-bond donor
interaction toward the imidazole nitrogen of olmesartan. The
pharmacophore model (Figure 2) assumes that interactions of
the carboxylate and the carbonyl moieties are essential
pharmacophore features, suggesting a certain degree of
similarity between the pharmacophores of AT1 and BLT2.
Notably, the most potent BLT2 agonist 8f displays low
nanomolar inhibitory activity toward AT1 (IC50 = 15 nM). In
contrast, regarding BLT1 activity, all compounds resulted in
being inactive. All in all, a series of 12 irbesartan (1) derivatives
was investigated and the first key structural features for activity
have been identified. The initial SARs of the irbesartan scaffold
are summarized in Figure 3.
In order to investigate the potential of irbesartan and the
most potent derivative of the series, 8f, as well as BLT2 agonist
CAY10583 to promote epithelial cell proliferation, the cell line
HCT116 was treated with indicated concentrations of the
compounds alone or in combination with the BLT2 antagonist
induced effects on epithelial colon cell proliferation were
abrogated by the BLT2 antagonist Ly255283 and this effect
was significant for irbesartan and 8f (0.1, 0.3, and 1 μM). The
application of the antagonist alone did not affect HCT116 cell
proliferation.
In conclusion, we were able to identify AT1 receptor
antagonists as BLT2 agonists using virtual screening of the
repurposing library. Among them, irbesartan showed the
highest potency. Preliminary SAR investigations led to the
identification of more potent irbesartan derivatives, which
displayed good activity in a functional assay. Furthermore,
irbesartan and 8f were able to promote the proliferation of
colon epithelial cells, which makes them an interesting option
for further investigation in the context of intestinal lesions.
D
https://doi.org/10.1021/acsmedchemlett.1c00240
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
pubs.acs.org/acsmedchemlett
Letter
Alexander Kaps − Fraunhofer Institute for Translational
Medicine and Phamacology ITMP, 60596 Frankfurt am
Main, Germany; Institute of Pharmaceutical Chemistry,
Goethe University Frankfurt, 60438 Frankfurt am Main,
Germany
Rinusha Rajkumar − Fraunhofer Institute for Translational
Medicine and Phamacology ITMP, 60596 Frankfurt am
Main, Germany; Institute of Pharmaceutical Chemistry,
Goethe University Frankfurt, 60438 Frankfurt am Main,
Germany
Ting Liu − Fraunhofer Institute for Translational Medicine
and Phamacology ITMP, 60596 Frankfurt am Main,
Germany; Institute of Pharmaceutical Chemistry, Goethe
University Frankfurt, 60438 Frankfurt am Main, Germany
Robert Furst − Institute of Pharmaceutical Biology, Goethe
̈
University Frankfurt, 60438 Frankfurt am Main, Germany
Dieter Steinhilber − Fraunhofer Institute for Translational
Medicine and Phamacology ITMP, 60596 Frankfurt am
Main, Germany; Institute of Pharmaceutical Chemistry,
Goethe University Frankfurt, 60438 Frankfurt am Main,
Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acsmedchemlett.1c00240
Author Contributions
Figure 4. Proliferation of HCT116 colon epithelial cells induced by
BLT2 agonists. The cells were seeded at a density of 5 × 103 cells per
well in 96-well plates. After 72 h of incubation, the cells were treated
with indicated concentrations of CAY10583, irbesartan, and 8f alone
or in combination with the BLT2 antagonist Ly255283 (1 μM) for 24
h. After 20 h, CellTiterBlue reagent was added to the cells for 4 h.
Fluorescent resorufin was measured using a plate reader. Data are
expressed as mean SEM; n = 3; ns = not significant; *p ≤ 0.05 vs
∥V. H.-O. and J.H. contributed equally. All authors have given
approval to the final version of the manuscript.
Funding
This research was supported by the Landes-Offensive zur
Entwicklung Wissenschaftlich-okonomischer Exzellenz
(LOEWE) Research Centre for Translational Medicine and
Pharmacology of the State of Hessen, Germany and Deutsche
Forschungsgemeinschaft (DFG, DFG-RBFR joint project
PR1405/8-1, Heisenberg-Professur PR1405/7-1; SFB 1039
TP A02 and TP A07).
̈
#
ctrl; p ≤ 0.05 vs CAY10583/irbesartan/8f alone.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acsmedchemlett.1c00240.
■
Notes
sı
The authors declare the following competing financial
interest(s): V.H.-O., J.H., D.S., and E.P have a patent
application that covers the composition of matter for BLT2
agonists.
Synthesis methods and characterization of intermediate
and final compounds; IP-One assay; proliferation assay
(PDF)
ABBREVIATIONS
■
Full list of virtual screening hits (PDF)
12-HHT, 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid;
AT1, angiotensin II receptor type 1; bFGF, basic fibroblast
growth factor; BLT1, leukotriene B4 receptor type 1; BLT2,
leukotriene B4 receptor type 2; CAY10583, 4′-((N-
phenylpentanamido)methyl)-[1,1′-biphenyl]-2-carboxylic
acid; IP-1, inositol monophosphate; LTB4, leukotriene B4;
TGF-β1, transforming growth factor beta 1.
AUTHOR INFORMATION
Corresponding Author
■
Ewgenij Proschak − Fraunhofer Institute for Translational
Medicine and Phamacology ITMP, 60596 Frankfurt am
Main, Germany; Institute of Pharmaceutical Chemistry,
Goethe University Frankfurt, 60438 Frankfurt am Main,
Germany; orcid.org/0000-0003-1961-1859;
Email: proschak@pharmchem.uni-frankfurt.de
REFERENCES
■
(1) Yokomizo, T.; Kato, K.; Terawaki, K.; Izumi, T.; Shimizu, T. A
Second Leukotriene B(4) Receptor, BLT2. A New Therapeutic
Target in Inflammation and Immunological Disorders. J. Exp. Med.
2000, 192 (3), 421−432.
(2) Yokomizo, T. Two Distinct Leukotriene B4 Receptors, BLT1
and BLT2. J. Biochem. 2015, 157 (2), 65−71.
Authors
Victor Hernandez-Olmos − Fraunhofer Institute for
Translational Medicine and Phamacology ITMP, 60596
Frankfurt am Main, Germany
Jan Heering − Fraunhofer Institute for Translational Medicine
and Phamacology ITMP, 60596 Frankfurt am Main,
Germany; orcid.org/0000-0002-4922-1993
Iris Bischoff-Kont − Institute of Pharmaceutical Biology,
Goethe University Frankfurt, 60438 Frankfurt am Main,
Germany
(3) Yokomizo, T. Leukotriene B4 Receptors: Novel Roles in
Immunological Regulations. Adv. Enzyme Regul. 2011, 51 (1), 59−64.
(4) Okuno, T.; Iizuka, Y.; Okazaki, H.; Yokomizo, T.; Taguchi, R.;
Shimizu, T. 12(S)-Hydroxyheptadeca-5Z, 8E, 10E-Trienoic Acid Is a
Natural Ligand for Leukotriene B4 Receptor 2. J. Exp. Med. 2008, 205
(4), 759−766.
E
https://doi.org/10.1021/acsmedchemlett.1c00240
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
pubs.acs.org/acsmedchemlett
Letter
(5) Luo, L.; Tanaka, R.; Kanazawa, S.; Lu, F.; Hayashi, A.;
Yokomizo, T.; Mizuno, H. A. Synthetic Leukotriene B4 Receptor
Type 2 Agonist Accelerates the Cutaneous Wound Healing Process in
Diabetic Rats by Indirect Stimulation of Fibroblasts and Direct
Stimulation of Keratinocytes. J. Diabetes Complications 2017, 31 (1),
13−20.
(6) Zinn, S.; Sisignano, M.; Kern, K.; Pierre, S.; Tunaru, S.; Jordan,
H.; Suo, J.; Treutlein, E.-M.; Angioni, C.; Ferreiros, N.; Leffler, A.;
DeBruin, N.; Offermanns, S.; Geisslinger, G.; Scholich, K. The
Leukotriene B4 Receptors BLT1 and BLT2 Form an Antagonistic
Sensitizing System in Peripheral Sensory Neurons. J. Biol. Chem.
2017, 292 (15), 6123−6134.
(7) Guriec, N.; Le Jossic-Corcos, C.; Simon, B.; Ianotto, J.-C.;
̈
Tempescul, A.; Dréano, Y.; Salaun, J.-P.; Berthou, C.; Corcos, L. The
Arachidonic Acid-LTB4-BLT2 Pathway Enhances Human B-CLL
Aggressiveness. Biochim. Biophys. Acta, Mol. Basis Dis. 2014, 1842
(11), 2096−2105.
(8) Mathis, S. P.; Jala, V. R.; Lee, D. M.; Haribabu, B. Nonredundant
Roles for Leukotriene B4 Receptors BLT1 and BLT2 in Inflammatory
Arthritis. J. Immunol. 2010, 185 (5), 3049−3056.
(9) Matsumoto, Y.; Matsuya, Y.; Nagai, K.; Amagase, K.; Saeki, K.;
Matsumoto, K.; Yokomizo, T.; Kato, S. Leukotriene B4 Receptor
Type 2 Accelerates the Healing of Intestinal Lesions by Promoting
Epithelial Cell Proliferation. J. Pharmacol. Exp. Ther. 2020, 373 (1),
1−9.
(10) Hernandez-Olmos, V.; Heering, J.; Planz, V.; Liu, T.; Kaps, A.;
Rajkumar, R.; Gramzow, M.; Kaiser, A.; Schubert-Zsilavecz, M.;
Parnham, M. J.; Windbergs, M.; Steinhilber, D.; Proschak, E. First
Structure-Activity Relationship Study of Potent BLT2 Agonists as
Potential Wound-Healing Promoters. J. Med. Chem. 2020, 63 (20),
11548−11572.
(11) Pushpakom, S.; Iorio, F.; Eyers, P. A.; Escott, K. J.; Hopper, S.;
Wells, A.; Doig, A.; Guilliams, T.; Latimer, J.; McNamee, C.; et al.
Drug Repurposing: Progress, Challenges and Recommendations. Nat.
Rev. Drug Discovery 2019, 18 (1), 41−58.
(12) Corsello, S. M.; Bittker, J. A.; Liu, Z.; Gould, J.; McCarren, P.;
Hirschman, J. E.; Johnston, S. E.; Vrcic, A.; Wong, B.; Khan, M.;
Asiedu, J.; Narayan, R.; Mader, C. C.; Subramanian, A.; Golub, T. R.
The Drug Repurposing Hub: A next-Generation Drug Library and
Information Resource. Nat. Med. 2017, 23 (4), 405−408.
(13) Giusti, F.; Casiraghi, M.; Point, E.; Damian, M.; Rieger, J.; Bon,
̀
C. L.; Pozza, A.; Moncoq, K.; Baneres, J.-L.; Catoire, L. J. Structure of
the Agonist 12-HHT in Its BLT2 Receptor-Bound State. Sci. Rep.
2020, 10 (1), 2630.
(14) Kim, M.; Wei, J.-D.; Harmalkar, D. S.; Goo, J.-I.; Lee, K.; Choi,
Y.; Kim, J.-H.; Cho, A. E. Elucidation of Mechanism for Ligand
Efficacy at Leukotriene B4 Receptor 2 (BLT2). ACS Med. Chem. Lett.
2020, 11 (8), 1529−1534.
(15) Zhang, H.; Unal, H.; Desnoyer, R.; Han, G. W.; Patel, N.;
Katritch, V.; Karnik, S. S.; Cherezov, V.; Stevens, R. C. Structural
Basis for Ligand Recognition and Functional Selectivity at
Angiotensin Receptor. J. Biol. Chem. 2015, 290 (49), 29127−29139.
F
https://doi.org/10.1021/acsmedchemlett.1c00240
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX