Novel amide and imidazole compounds as potent hematopoietic prostaglandin D2 synthase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2020.127759

In seeking novel and potent small molecule hematopoietic prostaglandin D₂ synthase (H-PGDS) inhibitors as potential therapies for PGD₂-mediated diseases and conditions, we explored a series comprising multiple aryl/heteroaryl rings attached in a linear arrangement. Each compound incorporates an amide or imidazole “linker” between the pyrimidine or pyridine “core” ring and the “tail” ring system. We synthesized and screened twenty analogs by fluorescence polarization binding assay, thermal shift assay, glutathione S-transferase inhibition assay, and a cell-based assay measuring suppression of LPS-induced PGD₂ stimulation. Amide analogs show ten-fold greater shift in the thermal shift assay in the presence of glutathione (GSH) versus the same assay run in the absence of GSH. The imidazole analogs did not produce a significant change in thermal shift between the two assay conditions, suggesting a possible stabilization effect of the amide linker in the synthase-GSH-inhibitor complex. Imidazole analog 23, (KMN-010034) demonstrates superior potency across the in vitro assays and good in vitro metabolic stability in both human and guinea pig liver microsomes.

Full text of DOI:10.1016/j.bmcl.2020.127759

Bioorg. Med. Chem. Lett. 34 (2021) 127759
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel amide and imidazole compounds as potent hematopoietic
prostaglandin D2 synthase inhibitors
Kirk L. Olson*, Melissa C. Holt, Fred L. Ciske, James B. Kramer, Paige E. Heiple,
Margaret L. Collins, Carrie M. Johnson, Chi S. Ho, M. Ines Morano, Stephen D. Barrett
Cayman Chemical Company, Inc., 1180 East Ellsworth Rd., Ann Arbor, MI, USA
A R T I C L E I N F O
A B S T R A C T
Keywords:
In seeking novel and potent small molecule hematopoietic prostaglandin D2 synthase (H-PGDS) inhibitors as
potential therapies for PGD2-mediated diseases and conditions, we explored a series comprising multiple aryl/
heteroaryl rings attached in a linear arrangement. Each compound incorporates an amide or imidazole “linker”
between the pyrimidine or pyridine “core” ring and the “tail” ring system. We synthesized and screened twenty
analogs by fluorescence polarization binding assay, thermal shift assay, glutathione S-transferase inhibition
assay, and a cell-based assay measuring suppression of LPS-induced PGD2 stimulation. Amide analogs show ten-
fold greater shift in the thermal shift assay in the presence of glutathione (GSH) versus the same assay run in the
absence of GSH. The imidazole analogs did not produce a significant change in thermal shift between the two
assay conditions, suggesting a possible stabilization effect of the amide linker in the synthase-GSH-inhibitor
complex. Imidazole analog 23, (KMN-010034) demonstrates superior potency across the in vitro assays and
good in vitro metabolic stability in both human and guinea pig liver microsomes.
Hematopoietic D2 synthase
H-PGDS
Prostaglandin D2
PGD2
Structure-activity-relationship
SAR
Introduction
generation human H-PGDS inhibitors identified. HQL-79 inhibits H-
PGDS competitively with PGH 2 and possesses moderate potency with a Ki
Prostaglandin D2 (PGD2) is released in large quantities during allergic
and asthmatic anaphylaxis from activated mast cells, reaching levels
100–1000 times higher than those produced by platelets, macrophages,
T-helper and dendritic cells.1 PGD2 also plays a detrimental pro-
inflammatory role in systemic mastocytosis, rheumatoid arthritis, and
Duchenne’s muscular dystrophy.2,3 PGD2 synthesis from the cyclic endo-
peroxide arachidonic acid (AA) metabolite, prostaglandin H2 (PGH2), is
catalyzed by two enzymes, lipocalin-type PGD2-synthase (L-PGDS) and
hematopoietic-type PGD-synthase (H-PGDS) (Scheme 1).4–6 L-PGDS
expression is largely localized to the brain, whereas H-PGDS expression
occurs primarily within the peripheral tissues.6 PGD2 is the endogenous
activating ligand for two prostaglandin receptors, PGD2 receptor 1 (DP1)
and PGD2 receptor 2 (DP2 or CRTH2), where these receptors mediate
complex downstream effects which can be pro-inflammatory or anti-
inflammatory in various instances.7,8 H-PGDS is therefore a central pro-
tein target for development of selective, potent inhibitors for therapeutic
use against PGD2-mediated diseases and conditions.
of 5
μ
M.9 Surface plasmon resonance (SPR) revealed that HQL-79 bound
H-PGDS with 12-fold higher affinity in the presence of GSH and Mg2+ than
in their absence, supporting that HQL-79 binding is stabilized by enzyme-
cofactor-inhibitor interactions, perhaps by a network of hydrogen bonds.9
GlaxoSmithKline, Sanofi, Evotec, Pfizer, Asahi Kasei, and AstraZe-
neca have investigated H-PGDS as a therapeutic target.3,9–17 Fig. 1 dis-
plays some of the compound leads generated from the pharma programs.
Though potencies have attained the low- to sub-nM IC50 range, none has
advanced through FDA approval. Structural similarities between the
program leads are evident with most inhibitors having a high degree of
aromaticity. The structures mainly comprise three components, an ar-
omatic head group, a linker moiety (often an amide), and a tail portion.
Compound 7, developed by Sanofi, incorporates a 5-(2-hydroxypropan-
2-yl)-1,2,4-oxadiazol-3-yl)-phenyl tail moiety, wherein the oxadiazole
ring imparts improved metabolic stability benefits over unsubstituted
and other substituted phenyl tail group-bearing analogs.16,17
We sought to optimize the physicochemical and pharmacokinetic
properties of a series of multiheteroaryl H-PGDS inhibitors disclosed
from our previous work.18 These predecessor inhibitors bear similarity
to Pfizer and Sanofi H-PGDS inhibitors 3 and 6, respectively.
H-PDGS is a sigma-type glutathione transferase that catalyzes the bi-bi
molecular reaction between nucleophilic cofactor glutathione (GSH) and
electrophilic substrate PGH2. HQL-79 (Fig. 1) was among the first-
* Corresponding author.
E-mail address: kolson@caymanchem.com (K.L. Olson).
https://doi.org/10.1016/j.bmcl.2020.127759
Received 26 October 2020; Received in revised form 17 December 2020; Accepted 20 December 2020
Available online 29 December 2020
0960-894X/© 2020 Elsevier Ltd. All rights reserved.

K.L. Olson et al.
Bioorganic & Medicinal Chemistry Letters 34 (2021) 127759
Scheme 1. Arachidonate cyclooxygenase pathway formation of PGD2.
Fig. 1. Examples of known H-PGDS inhibitors.
Compounds of this series comprise a string of covalently linked aromatic
rings, including sequentially a phenyl or pyridyl “head” ring, a pyrimi-
dine or pyridine “core” ring, a “linker” 5-membered heterocyclic ring in
place of the published amide linker, and a “tail” group typically
comprising a pyridine, substituted phenyl, or unsubstituted phenyl ring.
We explored the potential of the 5-membered heterocyclic ring linkers,
such as imidazole and thiazole, to eliminate the possibility of amidase-
mediated hydrolytic cleavage pathway of metabolism. We found the
imidazole linkers in place of amide maintained the high potencies of the
amide series, though we observed no benefit to solubility or metabolic
stability.18 In this work we generated a series of 20 new multiheteroaryl
analogs consisting of various combinations of head-core-linker-tail
while incorporating or not incorporating the 5-(2-hydroxypropan-2-
yl)-1,2,4-oxadiazol-3-yl in the tail moiety (Table 1). We prepared amide
linker-bearing and parallel imidazole linker-bearing analogs to assess
impact of this difference on activity profiles.
Scheme 3. Synthesis of analogs 7, 13–15.
15 (Scheme 3).
We constructed the new amide and imidazole analogs using the
routes illustrated in Schemes 2–8. Various head ring-core ring combi-
nations are commercially available as carboxylic acid intermediates,
including 6-phenylnicotinic acid (9a), 2,2′-bipyridine-5-carboxylic acid
(10a), 2-pyridin-2-ylpyrimidine-5-carboxylic acid (11a), and 2-phenyl-
5-pyrimidinecarboxylic acid (12a). We employed two strategies for
preparing the amide analogs. Direct amide coupling with benzylamine
provides amide linker-bearing compounds 9–12 (Scheme 2).
For the imidazoles, Weinreb amide activation of the head-core-
carboxylic acid intermediates followed by methyl lithium addition
provided the key ketone intermediates (Scheme 4). The head-core-
methyl ketone intermediates were subsequently brominated using tet-
rabutylammonium tribromide, forming the
α
-bromo ketone intermedi-
ate. Reaction of the
α
-bromo ketone intermediates with benzamidine
provided compounds 16, 17, 18, and 19. Phenyl-pyrimidyl intermediate
(19c) served as the key intermediate for the synthesis of many of the
compounds in Table 1, including the 3-pyridyl imidazole analog 24, and
the 3-pyridyl thiazole analog 25.
Reacting the α-bromo ketones (16c, 17c, and 19c) with 3-cyanoben-
zamidine provided a handle for synthesis of the tail region for com-
pounds 20, 21, and 23 (Scheme 5). The cyano intermediates were
converted to N-hydroxybenzimidamides 20b, 21b, and 23b, which were
subsequently cyclized in a base catalyzed reaction with 2-acetoxyisobu-
tyryl chloride, resulting in the formation of the protected 1,2,4-oxadia-
zole ring, providing the tail intermediates 20c-23c. Finally, removal of
the acetyl ester afforded compounds 20–23.
Scheme 2. Synthesis of analogs 9–12.
Formation of the
the pyridyl-pyrimidine head group series when using the method in
Scheme 5. Consequently, an alternative route towards the -bromo ke-
tone was employed to generate final analog 22 (Scheme 6). Suzuki-
α-bromo ketone was typically very low yielding for
We approached the amide linker-phenyl-oxadiazole-isopropanol-tail
combination through the synthetic construction of the tail, following a
published method.16,17 Subsequent amide coupling to the various
commercially available head groups affords compounds 7, 13, 14, and
α
2

K.L. Olson et al.
Bioorganic & Medicinal Chemistry Letters 34 (2021) 127759
Scheme 4. Synthesis of analogs 16–19, 24 and 25.
Scheme 5. Synthesis of analogs 20, 21 and 23.
Scheme 6. Synthesis of analog 22.
Miyaura coupling between the pyridine-2-boronic acid (22a) and 5-
bromo-2-iodopyrimidine (22b) provided intermediate 5-bromo-2-(pyri-
din-2-yl)pyrimidine (22c). Subjection of 22c to Stille conditions affor-
ded the vinyl ether, which is readily brominated with N-
bromosuccinimide. Formation of the imidazole through reaction with
benzamidine yields 22f. Likewise, the tail region of 22 is assembled in an
identical fashion to that which is depicted in Scheme 5.
Methyl substitution of the imidazole linker ring required alternate
synthetic routes (Schemes 7 and 8). Commercially available 4-methyl-2-
phenyl-1H-imidazole (26a) was benzyl-protected at the imidazole N1
position. Palladium catalyzed direct arylation between imidazole 26b
and commercially available 5-bromo-2-phenylbromide (26c) affords
26d. Deprotection of 26d by hydrogenation yielded analog 26.
Scheme 8. Synthesis of analog 27.
Scheme 7. Synthesis of analog 26.
3

K.L. Olson et al.
Bioorganic & Medicinal Chemistry Letters 34 (2021) 127759
The synthesis of 1-methyl substituted imidazole analog 27 is shown
Compound screening was performed in a multi-assay format to
reduce the risk of false positives and negatives, with the results dis-
played in Table 1. Overall, the screening paradigm grouped together a
competitive binding assay (fluorescence polarization binding assay, FP),
a direct-binding assay (TSA/ThermoFluor), a kinetic inhibition assay
(GSTase), and a cell-based assay (suppression of LPS-induced PGD2
stimulation, PGD2 levels measured by ELISA). Rank-order of compounds
was performed using FP derived IC50, melting temperature shift (ΔTm,
in Scheme 8. 1-Methyl-2-phenyl-1H-imidazole (27b) was obtained via
direct methylation of 2-phenyl-1H-imidazole (27a) with iodomethane.
Palladium catalyzed direct arylation between imidazole 27b and 26c
afforded 27.
Overall, synthesized analogs in this data set compared individual ef-
fects of head-core-linker-tail modifications on activity profiles with the
goal to develop potent, and metabolically stable lead H-PGDS inhibitor2s.
Table 1
SAR of compounds 7, 9–27. FP binding assay IC50 and CBA IC50 values were calculated using nonlinear regression in GraphPad Prism 7.02 software and are presented
as mean ± SEM of (n replicates). ND refers to values that were not determined. Statistical analysis was performed using one-way ANOVA controlling false-discovery
rate of multiple comparisons using two-stage linear procedure by Benjamini, Krieger, and Yekutieli. Superscripts indicate that P < 0.05 for comparisons with the
following compounds 9 (a), 10 (b), 11 (c), 12 (d), 13 (e), 14 (f), 7 (g), 15 (h), 16 (i), 17 (j), 18 (k), 19 (l), 20 (m), 21 (n), 22 (o), 23 (p), 24 (q), 25 (r), 26 (s), 27(t).
Compounds which significantly violated the sphericity assumption were excluded from statistical analysis including 18, 22 from FP statistics and 22 from CBA sta-
tistics. Statistics are provided for compounds with > 80% inhibition in GSTase assay as well.
No.
(9)
X
C
Y
C
R1
Z
C
R2
H
FP IC50 (nM)
ΔTm (◦C)
ΔTm (◦C)
% GSTase Inhibition
CBA IC50 (nM)
w/ 1 mM GSH
122 ± 51.2 (6)c-j,l,m,p,q-
0.3 ± 0 (3)
3.0 ± 0 (3)
2.8 ± 0.2 (3)
4.2 ± 0 (3)
4.6 ± 0.1 (3)
3.3 ± 0 (3)
2.8 ± 0.1 (3)
5.1 ± 0 (3)
40.4 ± 1.06 (3)
1,234 ± 151 (4)b-n,p,q,s,t
s
(10)
(11)
(12)
(13)
(14)
(7)
N
N
C
C
N
N
C
C
C
N
N
C
C
N
N
C
C
C
C
C
C
C
C
C
H
H
H
80.7 ± 11.7 (6)c,d,g,h,l,p,
0.1 ± 0.1 (3)
0.2 ± 0.1 (3)
0.4 ± 0.1 (3)
0.2 ± 0.1 (3)
0.1 ± 0.1 (3)
0.5 ± 0.1 (3)
0.4 ± 0.1 (3)
3.2 ± 0.1 (3)
19.2 ± 1.62 (3)
452.8 ± 118.2 (4)a,c-e,g-n,p,q,s
35.71 ± 4.21 (7)a,b,e,f,k,s,t
23.91 ± 8.53 (11) a,b,e,f,k,s,t
807.75 ± 84.99 (4)a-d,f-n,p,q,s
r
7.14 ± 2.06 (7)a,b,n,r
11.7 ± 1.50 (13)a,b,n,r
27.7 ± 4.32 (5)a,r
71.3 ± 1.91 (3)
82.5 ± 0.51 (3)g,i,l,p
62.4 ± 0.58 (3)
55.5 ± 17.1 (6)a,p,r
7.48 ± 1.53 (5)a,b,n,r
7.18 ± 1.56 (9)a,b,n,r
31.6 ± 10.3 (6)a,r
47.2 ± 6.48 (3)
327.75 ± 41.02 (4)a,c-e,g,h,k,n,p,
s,t
90.9 ± 1.33 (3)d,h,l,m,s
83.9 ± 0.61 (3)g,l,p,s
85.2 ± 0.20 (3)d,g,l,m,p,s
11.61 ± 1.67 (10)a,b,e,f,k,s,t
9.86 ± 1.54 (16)a,b,e,f,k,s,t
40.5 ± 2.1 (4)a,b,e,k,s,t
(15)
(16)
4.95 ± 0.15
(3)
H
H
H
H
4.4 ± 0.1 (3)
5.2 ± 0.1 (3)
0.6 ± 0 (3)
(17)
(18)
(19)
(20)
(21)
(22)
(23)
N
N
C
C
N
N
C
C
N
N
C
C
N
N
C
C
C
C
C
C
C
37.2 ± 6.31 (5)a,r
4.2 ± 0 (3)
0.2 ± 0.1 (3)
3.6 ± 0 (3)
4.3 ± 0.1 (3)
4.8 ± 0 (3)
0.4 ± 0.1 (3)
6.9 ± 0.1 (3)
73.5 ± 4.26 (3)
18.2 ± 0.47 (3)
44.5 ± 12.7 (4)a,b,e,k,s,t
5,056 ± 622.7 (4)a-j,l-n,p,q,s,t
59.00 ± 12.16 (6)a,b,e,k,s,t
72.0 ± 14.13 (7)a,b,e,k,s,t
23.41 ± 5.68 (7)a,b,e,f,k,s,t
ND
1,765 ± 1,179 (2)
8.88 ± 2.9 (9)a,b,n,r
35.4 ± 17.3 (3)a,r
3.8 ± 0.1 (3)
5.2 ± 0.1 (3)
5.4 ± 0 (3)
94.5 ± 0.31 (3)d,g,h,i,m,p,
s
83.5 ± 0.29 (3)g,i,l,p,s
76.1 ± 4.62 (3)
78.6 ± 18.3 (6)c,d,g,h,l,r
3,203 ± 1,214 (3)
5.88 ± 1.18 (15)a,b,f,n,r,t
0.6 ± 0 (3)
25.5 ± 14.9 (3)
7.1 ± 0.1 (3)
92.1 ± 0.66 (3)d,h,i,l,m
20.67 ± 3.38 (18)a,b,e,f,k,s,t
(continued on next page)
4

K.L. Olson et al.
Bioorganic & Medicinal Chemistry Letters 34 (2021) 127759
Table 1 (continued)
No.
X
Y
R1
Z
R2
FP IC50 (nM)
ΔTm (◦C)
ΔTm (◦C)
% GSTase Inhibition
CBA IC50 (nM)
w/ 1 mM GSH
(24)
C
N
N
13.2 ± 5.42 (3)a,r
4.9 ± 0.1 (3)
5.7 ± 0 (3)
65.1 ± 1.09 (3)
12.5 ± 4.5 (2)a,b,e,k,s,t
(25)
(26)
C
C
N
N
N
C
257 ± 159 (2)a-j,l-n,p,q,s,t
30.8 ± 10.2 (3)a,r
2.1 ± 0 (3)
2.2 ± 0.1 (3)
4.5 ± 0 (3)
29.5 ± 1.41 (3)
>5,000 (2)
H
H
4.3 ± 0.1 (3)
81.5 ± 0.98 (3)g,h,i,l,m,p
3,742.5 ± 338.5 (2)a-n,p,q,t
(27)
C
N
C
63.1 ± 19.4 (3)p,r
3.1 ± 0.1 (3)
3.4 ± 0.1 (3)
38.4 ± 7.8 (3)
723.5 ± 95.5 (2)a,c,d,f-n,p,q,s
◦C) in the presence/absence of GSH, percent GSTase inhibition, and cell-
based assay (CBA) derived IC50
still significantly decrease cell activity.
.
Lastly, analog 23, KMN-010034 showed good in vitro stability with a
half-life > 60 min when tested in human liver microsomes. Unfortu-
nately, we achieved a maximum aqueous KMN-010034 concentration
Analogs bearing the pyrimidine ring core generally excel in H-PGDS
binding and cellular potencies over their corresponding pyridine ana-
logs with pyrimidines 23, 11, 15, 7, 19, and 12 representing the six most
potent compounds of the twenty tested in the FP binding assay, and all
these except for 19 representing the five most potent in the CBA
(Table 1). The phenyl(head)-pyrimidine(core)-linker-5-(2-hydroxypropan-
2-yl)-1,2,4-oxadiazol-3-yl)-phenyl(tail) combination represented by amide
linker analog 15 and imidazole linker analog 23 is quite favorable,
providing two of the most potent compounds in the FP binding assay, CBA,
and GSTase inhibition assay while demonstrating relatively strong shifts in
the TSA.
of only 3.3 μM in PBS @ pH 7.4. Replacement of the phenyl head ring
with 2-pyridyl offers an aqueous solubility benefit. We observed
improved solubility for the 2-pyridyl head ring analog of 23, compound
22, for which we achieved a maximum aqueous concentration of 17.5
μM under the same conditions.
In one of the most clear and dramatic observations of the series SAR,
the pyridine-pyrimidine-imidazole-tail group combination as repre-
sented by analogs 18 and 22 is detrimental to binding and activity across
the panel of assays. Simple replacement of any one of the three nitrogen
atoms of the head group-core ring component with a carbon atom (17,
19, 21, and 23) restores orders of magnitude to the FP and CBA IC50s
while also recovering significant activity in both the TSA and GSTase
assay. The detrimental impact of the pyridine-pyrimidine combination
on H-PGDS binding and activity is not observed when the linker is the
amide, as observed across the assay panel for two sets of compounds 10-
11-12, and 14–17-15. Interestingly, we observed a 10-fold increased
TSA shift for all eight amide linker analogs when the assay included a 1
mM concentration of the glutathione cofactor (GSH) over those shifts
observed when GSH was not added. The amide core displaying a
dependence upon GSH matches broadly with previously reported work
showing an enhancement in K in the presence of GSH.9 We did not
observe such a change, howeveri, in shift for heterocycle linker analogs.
The imidazole linked series displayed nearly an equivalent ΔTm in the
presence or absence of GSH (Fig. 2). This suggests that specific in-
teractions (perhaps hydrogen bonding interactions) between the
cofactor and amide group stabilize the cofactor-inhibitor-synthase
binding complex. Analog 23 displayed the largest Tm shift in the TSA,
6.9/7.1 ◦C, in the absence or presence of GSH, relative to all other
compounds screened. The observed T shift between the amide and
m
imidazole series suggested further study on the mode of inhibition was
needed. GSH competitive binding (imidazole series) versus non-
competitive binding (amide series) will be further investigated in an
upcoming publication.
Analogs 24-27 test variations of the 5-membered heterocycle linker-
tail group motif while maintaining the phenyl-pyrimidine head group-
core ring arrangement. The pyridin-3-yl tail of imidazole analog 24
imparts binding and activity across the assay panel. Replacing the
1-nitrogen atom of imidazole analog 24 with a sulfur atom to provide
thiazole analog 25 results in the significant loss of H-PGDS binding
potencies and activity, whereas methyl substitutions at various imid-
azole ring positions (analogs 26 and 27) slightly diminish binding yet
Fig. 2. A) Change in melting temperature observed in TSA to Apo H-PGDS. (B)
Change in melting temperature observe in TSA to Apo H-PGDS in the presence
of GSH. All error bars are SEM.
5

K.L. Olson et al.
Bioorganic & Medicinal Chemistry Letters 34 (2021) 127759
6 Urade Y, Eguchi N. Lipocalin-type and hematopoietic prostaglandin D synthases as a
novel example of functional convergence. Prostag Oth Lipid M. 2002;68–69:375–382.
https://doi.org/10.1016/S0090-6980(02)00042-4.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
7 Korbecki J, Baranowska-Bosiacka I, Gutowska I, et al. Cyclooxygenase pathways.
ACTA Biochim Pol. 2014;61(4):639–649. http://www.actabp.pl/pdf/4_2014/639.pdf.
8 Song W-L, Ricciotti E, Liang X, et al. L-PGDS but not H-PGDS deletion causes
hypertension and accelerates thrombogenesis in mice. J Pharmacol Exp Ther. 2018;
367(3):425–432. https://doi.org/10.1124/jpet.118.250936.
9 Aritake Kosuke, Kado Yuji, Inoue Tsuyoshi, Miyano Masashi, Urade Yoshihiro.
Structural and functional characterization of HQL-79, an orally selective inhibitor of
human hematopoietic prostaglandin D synthase. J Biol Chem. 2006;281(22):
15277–15286.
Acknowledgments
We thank Yoshi Urade for past guidance and insight. We thank former
project members for their research and dedication. We would especially
like to thank Kirk Maxey for his continued guidance and support. All
funds were R&D expenditures of Cayman Chemical Company, Inc.
10 Carron Chris P, Trujillo John I, Olson Kirk L, et al. Discovery of an oral potent
selective inhibitor of hematopoietic prostaglandin D synthase (HPGDS). ACS Med
Chem Lett. 2010;1(2):59–63. https://doi.org/10.1021/ml900025z.
11 Aldous, S. C., Jiang, J. Z., Lu, J. et al. Preparation of pyrimidine amide derivatives as
prostaglandin D synthase inhibitors. WO2007041634 A1, 2007.
12 Trujillo John I, Kiefer James R, Huang Wei, et al. Investigation of the binding pocket
of human hematopoietic prostaglandin (PG) D2 synthase (hH-PGDS): a tale of two
waters. Bioorg Med Chem Lett. 2012;22(11):3795–3799. https://doi.org/10.1016/j.
bmcl.2012.04.004.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bmcl.2020.127759.
13 Hohwy Morten, Spadola Loredana, Lundquist Britta, et al. Novel prostaglandin
d synthase inhibitors generated by fragment-based drug design. J Med Chem. 2008;51
(7):2178–2186. https://doi.org/10.1021/jm701509k.
14 Cadilla Rodolfo, Deaton David N, Do Young, et al. The exploration of aza-quinolines
as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors with low brain
exposure. Bioorg Med Chem. 2020;28(23):115791. https://doi.org/10.1016/j.
bmc.2020.115791.
References
1 Bochenek, G., E. Nizankowska, A. et al. Plasma 9alpha, 11beta-PGF2, a PGD2
metabolite, as a sensitive marker of mast cell activation by allergen in bronchial
asthma. Thorax 2004;59(6):459-464. http://dx.doi.org/10.1136/thx.2003.013573.
2 Kanaoka Y, Urade Y. Hematopoietic prostaglandin D synthase. Prostaglandins Leukot
Essent Fatty Acids. 2003;69(2–3):163–167. https://doi.org/10.1016/S0952-3278(03)
00077-2.
15 Takaya Daisuke, Inaka Koji, Omura Akifumi, et al. Characterization of crystal water
molecules in a high-affinity inhibitor and hematopoietic prostaglandin D synthase
complex by interaction energy studies. Bioorg Med Chem. 2018;26(16):4726–4734.
https://doi.org/10.1016/j.bmc.2018.08.014.
16 VanDeusen, C.L., Weiberth, F. J., Gill, H.S. et al. Phenyloxadiazole derivatives
as PGD inhibitors and their preparation, pharmaceutical compositions and use
in the treatment of allergic and inflammatory disorders. WO2011044307, 2011.
17 Weiberth Franz J, Yu Yong, Subotkowski Witold, Pemberton Clive. Demonstration on
pilot-plant scale of the utility of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as a
catalyst in the efficient amidation of an unactivated methyl ester. Org Process Res Dev.
2012;16(12):1967–1969. https://doi.org/10.1021/op300210j.
3 Thurairatnam S. Hematopoietic prostaglandin D synthase inhibitors. Prog Med Chem.
2012;51:97–133. https://10.1016/B978-0-12-396493-9.00004-2.
4 Kanaoka Yoshihide, Ago Hideo, Inagaki Eiji, et al. Cloning and crystal structure of
hematopoietic prostaglandin D synthase. Cell. 1997;90(6):1085–1095. https://doi.
org/10.1016/S0092-8674(00)80374-8.
5 Irikura D, Kumasaka T, Yamamoto M, et al. Cloning, expression, crystallization, and
preliminary X-ray analysis of recombinant mouse lipocalin-type prostaglandin D
synthase, a somnogen-producing enzyme. J Biochem. 2003;133(1):29–32. https://
doi.org/10.1093/jb/mvg006.
18 Endres G.W., Lee P.H., Olson K.L. et al. Multiheteroaryl compounds as inhibitors of
H-PGDS and their use for treating prostaglandin D2 mediated diseases. US 2013/
0079375 A1, 2013.
6