Discovery of MK-8318, a Potent and Selective CRTh2 Receptor Antagonist for the Treatment of Asthma

Article abstract of DOI:10.1021/acsmedchemlett.8b00145

A novel series of tricyclic tetrahydroquinolines were identified as potent and selective CRTh2 receptor antagonists. The agonism and antagonism switch was achieved through structure-based drug design (SBDD) using a CRTh2 receptor homologue model. The challenge of very low exposures in pharmacokinetic studies was overcome by exhaustive medicinal chemistry lead optimization through focused SAR studies on the tricyclic core. Further optimization resulted in the identification of the preclinical candidate 4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic acid (15c, MK-8318) with potent and selective CRTh2 antagonist activity and a favorable PK profile suitable for once daily oral dosing for potential treatment of asthma.

Full text of DOI:10.1021/acsmedchemlett.8b00145

Subscriber access provided by Kaohsiung Medical University
Letter
Discovery of MK-8318, a Potent and Selective CRTh2
Receptor Antagonist for the Treatment of Asthma
Xianhai Huang, Jason Brubaker, Wei Zhou, Purakkattle J. Biju, Li Xiao, Ning Shao, Ying Huang, Li
Dong, Zhidan Liu, Rema Bitar, Alexei V. Buevich, Joon Jung, Scott L. Peterson, John W Butcher,
Joshua Close, Michelle Martinez, Rachel N. MacCoss, Hongjun Zhang, Scott Crawford, Kevin D.
McCormick, Robert Aslanian, Ravi P Nargund, Craig Correll, Francois Gervais, Hongchen Qiu, Xiaoxin
Yang, Charles Garlisi, Diane Rindgen, Kevin M. Maloney, Phieng Siliphaivanh, and Anandan Palani
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.8b00145 • Publication Date (Web): 23 Jun 2018
Downloaded from http://pubs.acs.org on June 24, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 8
ACS Medicinal Chemistry Letters
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

ACS Medicinal Chemistry Letters
Page 2 of 8
1
2
3
4
5
6
7
8
9
Discovery of MK-8318, a Potent and Selective CRTh2 Receptor An-
tagonist for the Treatment of Asthma†
Xianhai Huang,1,* Jason Brubaker2 Wei Zhou,1 Purakkattle J. Biju,1 Li Xiao,1 Ning Shao,1 Ying
Huang,1 Li Dong,1 Zhidan Liu,1 Rema Bitar,1 Alexei Buevich,1 Joon Jung,2 Scott L. Peterson,2 John W.
Butcher,2 Joshua Close,2 Michelle Martinez,2 Rachel N. MacCoss,2 Hongjun Zhang,2 Scott Crawford,2
Kevin D. McCormick,1 Robert Aslanian,1 Ravi Nargund,1 Craig Correll,3 Francois Gervais,3 Hongchen
Qiu,4 Xiaoxin Yang,4 Charles Garlisi,4 Diane Rindgen,5 Kevin M. Maloney,6 Phieng Siliphaivanh,2 and
Anandan Palani1,*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1Discovery Chemistry, 4In Vitro Pharmacology, 5Drug Metabolism and Pharmacokinetics, 6Process Chemistry, MRL, 2015
Galloping Hill Road, Kenilworth, NJ 07033, USA
2Discovery Chemistry, 3Immunology, MRL, 33 Avenue Louis Pasteur, Boston, MA 02115, USA
†Dedicated to Professor E. J. Corey on the occasion of his 90th birthday
KEYWORDS: MK-8318, CRTh2 receptor, DP2 receptor, receptor antagonist, homology model, PK lead optimization,
pharmacokinetics, asthma, tetrahydroquinoline
ABSTRACT: A novel series of tricyclic tetrahydroquinolines were identified as potent and selective CRTh2 receptor antagonists.
The agonism and antagonism switch was achieved through structure based drug design (SBDD) using a CRTh2 receptor homolog
model. The challenge of very low exposures in pharmacokinetic studies was overcome by exhaustive medicinal chemistry lead
optimization through focused SAR studies on the tricyclic core. Further optimization resulted in the identification of the preclinical
candidate
4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic acid (15c, MK-8318) with potent and selective CRTh2 antagonist activity and a
favorable PK profile suitable for once daily oral dosing for potential treatment of asthma.
Asthma is a common chronic lung disease that inflames and
narrows the airways and affects millions of people of all ages
in all parts of the world. It is a cause of substantial burden to
society and often results in a reduced quality of life. It was
estimated in 2014 that about 334 million people worldwide
had asthma with a potential increase of incidences by 50%
every decade.1,2 For mildly asthmatic patients, the disease can
be well controlled by multiple treatment options such as in-
haled formulations including inhaled corticosteroids (ICS),
both short-acting beta agonists (SABAs) and long-acting beta
agonists (LABAs), long-acting muscarinic antagonists (LA-
MAs), and LABA/inhaled corticosteroid ICS fixed-dose com-
binations (FDCs).3,4 However, convenience and patient com-
pliance continue to be an issue with these treatments even
though non-steroid oral asthma medications such as leukotri-
ene receptor antagonists (e.g., montelukast) are available but
are used as a second-line treatment due to lower clinical effi-
cacy. For severe and refractory asthmatic patients, the treat-
ment options are more limited and biologic-based treatments
became available just recently.5,6 With such a global disease
burden and cause of suffering, unmet medical needs remain in
finding efficient treatments and control of asthma and other
allergic diseases. In recent years, the chemoattractant receptor
homologous molecule expressed on T-Helper type 2 (CRTh2)
receptor (alternatively DP2 receptor) antagonists have attract-
ed much attention from the pharmaceutical industry7,8 due to
their significant role in modulating allergic inflammation via
stimulation of Th2 cells, eosinophils and basophils. It has been
shown that the PGD2 induced chemotaxis, degranulation and
cytokine production are exclusively exerted through CRTh2
receptors, and modulation of CRTh2 receptors should result in
reducing excessive allergic responses and could be used for
the treatment of asthma.9,10,11 TP receptor antagonist (throm-
boxane receptor) ramatroban is marketed in Japan for the
treatment of allergic rhinitis and was considered as a potential
treatment of asthma. Its anti-allergic efficacy was believed to
be related to its moderate CRTh2 activity.12 Market research
indicates physicians and patients would welcome an improved
oral therapy. An oral CRTh2 antagonist has potential utility
for the mild asthmatics who prefer oral non-steroid control
over an inhaled option and/or who have not had an adequate
response to leukotriene receptor antagonists. This can be used
for patients who need greater control as add-on to ICS or
ICS/LABA or leukotrienes. Due to these potential clinical
benefits, many companies have since identified potent CRTh2
antagonists in recent years with about 20 of them having pro-
gressed into clinical development.13-17 At MRL, as an addition
to the Singulair® franchise, a CRTh2 antagonist was pro-
gressed to clinical trials (Figure 1. MK-7246) targeting asth-
ma.13,18 To continue the effort in this area, a backup program
was established in house with the goal to identify a CRTh2
antagonist suitable for once daily dosing which would be
ACS Paragon Plus Environment

Page 3 of 8
ACS Medicinal Chemistry Letters
structurally distinct from current clinical candidates.19 Herein,
philic alkyl groups were acceptable at this position with cy-
clobutyl and cyclopropyl derivatives being the most potent.
Polar substitutions were not well tolerated (data not shown)
which may be because this portion of the molecule occupies
the lipophilic region of the receptor. Based on the better bind-
ing activity of the cyclopropyl group, it was chosen as the
optimum substitution at this position for further SAR devel-
opment. The length of the acid side chain is important for ac-
tivity and a two carbon spacer was proven to be optimal
length. When the acid is three carbons away from the amide
carbonyl (Figure 4, 6 vs 9), the activity decreased. On the oth-
er hand, carbamates at the northern sidechain were acceptable
with a two atom spacer (7 vs 8).
1
2
3
4
5
6
7
8
we report our effort in identifying structurally novel MK-8318
as a potent and selective CRTh2 receptor antagonist suitable
for once-daily oral dosing.
In addition to the leads such as compound 119 generated
through in house compound screening, we decided to pursue a
literature based drug design strategy to generate a structurally
different lead. In this regard, tetrahydroquinoline CRTh2 an-
tagonists attracted our attention due to their unique structure
and potent binding and functional antagonist activity.20 Start-
ing from known compound 220 (Figure 2), extensive structural
overlay through conformational analysis identified fused tricy-
clic compound 3 as a potent CRTh2 ligand in the binding as-
say. However, to our surprise, when it was tested in the func-
tional cAMP assay with the agonist mode, this compound
turned out to be a functional partial agonist. It was known that
subtle structural changes might impact the properties of the
molecule to serve as an antagonist or agonist.19,21 To overcome
this problem, we decided to compare the structure with a
known CRTh2 agonist indomethacin22 in the CRTh2 homolog
model. It suggested that the aniline phenyl group in 3 was
overlapping with the methoxybenzene in indomethacin which
was occupying the agonist pocket of the receptor (Figure 3).
From the modeling study, we also noticed two key hydrogen
bond interactions (between side chain acid and Lys210, and
between benzocarbonyl and Tyr262) which were crucial for
activity based on future SAR studies. With this information in
mind, a smaller ethyl group was introduced (4) to minimize
the interaction in this region. To our delight, compound 4 in-
deed lacked agonist activity and was a potent CRTh2 antago-
nist in both binding and functional assays.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. Overlay of homology models of human CRTh2
in complex with indomethacin, 3, or 4 (stereochemistry as
drawn: 3aS,9R,9aR).a
aThe acid of three ligands forms a salt-bridge with Lys210 side-chain
amino group; benzocarbonyl of 3 and 4 makes hydrogen bond with
Tyr262 sidechain hydroxy group, shown with dashed lines. The area oc-
cupied by methoxybenzene of indomethacin was defined as agonist selec-
tivity pocket (circled), which is pointed toward TMH-6. Carbon atoms of
indomethacin are colored in cyan, 3 in orange and 4 in yellow.
Figure 1. Structures of MK-7246, in house CRTh2 antago-
nist, and indomethacin.
Table 1. Alkyl side chain modification of the northern por-
tion.
O
R
OH
N
N
Figure 2. Evolution of initial leads.
O
5a
O
OCF3
R
1
1
1
1
1
5a
5b
12
5c
50
5d
5e
8.6
Ki (nM)b
R
16
7.0
1
F3C
1
1
5f
64
5g
5h
Ki (nM)b
35
9.0
With multiple positions for SAR modifications in com-
pound 4, a systematic optimization strategy was taken to
quickly determine the essential pharmacophores at each por-
tion of the molecule (Figure 2, north, middle and south por-
tions.) before focused SAR to optimize overall profiles. Con-
sidering the profound effect of the exo-cyclic alkylamine on
the functional activity, we first started the optimization of the
northern portion of the molecule (Table 1, 5a-5h). Small lipo-
a. OCF3 benzamide was chosen to establish this SAR due to improved
rat PK comparing to simple benzamide from initial screening SAR.
b. The data is the mean of at least two determinations.
For the middle portion, both cyclobutyl- and cyclohexyl-
fused rings provided compounds having comparable binding
activity to the compound having a cyclopentyl-fused ring
ACS Paragon Plus Environment

ACS Medicinal Chemistry Letters
Page 4 of 8
(Figure 4, 10, 11 vs 9). However, the SAR is very narrow.
core at the southern portion was necessary in order to achieve
the desired binding and functional activity, but exposure in rat
PK still needed to be improved.
1
2
3
4
5
6
7
8
When small substitutions such as methyl and gem-dimethyl
were introduced to the cyclic alkyl rings in an effort to im-
prove the PK properties of the compounds, such substitutions
resulted in less active antagonists (data not shown). From the
point of view of improving the metabolic profile, we felt the
smaller cyclobutyl-fused ring might offer some advantages
and decided to fix it as the core structure while developing
SAR of the southern portion of the molecule.
Table 2. SAR of southern portion of the cyclobutyl fused
tricyclic core.
9
Figure 4. SAR of the acid side chain and tricyclic core.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 3. Modifications of southern portion of the cyclopen-
tyl fused tricyclic core.
Initial SAR efforts with amide substitutions at the southern
portion were promising. Aryl amides with different groups
were well tolerated and showed potent CRTh2 binding and
functional activity (Table 2, 12a-12d). Southern arylamides
also worked well with a northern carbamate acid side chain
(12e-12g) and had potent activity with all analogs showing
single digit nM binding potency. Compounds 12e and 12f also
met program activity target profile of single digit nM potency
in functional assay (cAMP and beta-arrestin) and EOS whole
blood assay (eosinophil shape change assay in human whole
blood). Unfortunately, when these compounds were tested in
rat PK studies,23 most of them had very poor exposure (AUC)
with the carbamate analogs the worst (12e, 12f). The analysis
of in vitro hepatocyte stability and PK parameters correlations
unfortunately failed to predict exposure in rat (data not
shown).
Presented with the poor PK results of the cyclobutyl fused
analogs, we decided to investigate the cyclopentyl fused core
to determine whether any improvement could be achieved and
hope a compound with improved PK exposure can be identi-
fied through the empirical study. In this regard, different sub-
stitutions were introduced at the southern part (Table 3, select-
ed examples.) Amides and carbamates were tolerated in terms
of activity (5d, 13a, 13d-13e), but rat PK exposure was still
poor. Elongated amide (13b) was not tolerated which con-
firmed the importance of the carbonyl group as indicated in
the homolog model. Urea 13c lost the binding activity by
about 10 fold. Heterocycle 13f gave reasonable binding activi-
ty, but functional activity decreased dramatically. Based on
these observations, an amide functionality off the tricyclic
To understand the cause of the poor PK properties even with
good solubility and permeability profiles, in vitro metabolite
ID studies in rat were carried out. The studies showed that the
major metabolic pathway was glucuronidation of the side
chain acid in addition to oxidative metabolism at the middle
core and southern region. In order to block or minimize acid
ACS Paragon Plus Environment

Page 5 of 8
ACS Medicinal Chemistry Letters
metabolism, different side chains were introduced to increase
analogs of compound 15c were prepared to see whether fur-
ther PK improvement could be achieved. But disappointingly,
these modifications again resulted in loss of binding activity
(Table 6, 16a-16f) and did not offer much improvement in PK
profile (data not shown), which again suggested a very narrow
SAR in this series.
1
2
3
4
5
6
7
8
steric hindrance and impact pKa of the acid (Table 4). Howev-
er, these modifications proved to be fruitless: removal of the
acid from the side chain resulted in much reduced functional
activity (14a; cAMP IC50 = 1840 nM); bulky side chains re-
sulted in loss of binding potency (14b-14d); aryl and heteroar-
yl linker analogs either lost binding activity (14e) or resulted
in partial agonism (14f). An acid bioisostere provided no ad-
vantage and reduced activity was observed (14g). To this
point, the SAR development had led us to a very narrow space
for improvement in terms of PK exposure profile. In review-
ing the PK data, a slight exposure (AUC) improvement in
compound 5d (Table 3) caught our attention and left us some
hope that there might be opportunity to identify compounds
with increased plasma exposure.
Table 5. Focused SAR of the phenyl ring of the cyclopentyl
fused tricyclic tetrahydroquinoline.
O
9
OH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
O
N
15
O
OCF3
Table 4. Acid side chain modifications.
cAMP
EOS rat AUC0-6h
-Arrestin
R1
a
a
Kia
a
IC50
IC50
(nM.h)b
IC50
14
N
2.3
110
4.0
8.0
59
Cl
R2
15a
15b
Ki (nM)d
26
No.
R1
R2
3.0
5.0
1.7
3.5
6.2
7.9
43
F
F
1
O
14aa
N
O
Ph
3350c
1
1
O
15c
15d
OH
Cbz
510
14b
14c
F
N
1
O
O
O
3.4
8.4
18
12
12
6.2
1050
Cl
1
O
O
OH
OH
Cbz
F
N
O
82
1870d
1
2.4
1
OCF3 = SCF3
7800
Cbz
14d
14e
N
1
15e
a. in nM; The data is the mean of at least two determinations.
b. 0.5 mpk IV. c. 3 mpk IV. d. 2 mpk IV.
1
OH
O
840
51
O
OCF3
N
O
O
Table 6. Targeted modifications based on compound 15c.
1
OH
1
14fb
N
O
Cbz
S
N
1
1
14gc
N
N
1
O
98
NH
N
N
OCF3
a. EOS shape IC50 = 4930 nM, racemic. b. cAMP IC50 = 2920 nM;
cAMP agonist EC50 = 12 nM, racemic. c. All cis racemic. d. The
data is the mean of at least two determinations.
Based on this observation, we decided to explore the modi-
fication of the phenyl ring in the middle core portion, an area
we have not explored yet. In this regard, small electron with-
drawing groups such as F and Cl atoms were introduced first
to block a potential metabolic hot spot and to affect overall
electronic properties of the core which might impact PK (Ta-
ble 5). To our delight, most of these compounds retained very
good biological activity and a few of them provided improved
exposure when dosed in rat, with compound 15c being the best
(Table 5, 15c-15e). To capitalize on this effort, a few close
To this end, compound 15c stood out as one of the best
molecules from the rat PK evaluation. It was further profiled
ACS Paragon Plus Environment

ACS Medicinal Chemistry Letters
Page 6 of 8
in rat, dog and monkey. The compound demonstrated overall
was hydrolyzed to give final product 15c. This synthetic se-
quence was very efficient and analogs could be prepared
readily.
1
2
3
4
5
6
7
8
good pharmacokinetic characteristics including oral bioavaila-
bility and half-life across the species (Table 7) which allowed
once daily oral dosing in human. In addition to single digit nM
potency in all assays meeting program activity target profile
(Ki, cAMP, beta-arrestin, and EOS shape change), compound
15c also showed clean profiles in ancillary studies (such as
P450 enzyme inhibition, TDI, and PXR) and excellent selec-
tivity against other related prostanoid receptors (Please see
Supporting Information for ancillary profiles summary.).
Based on the good overall profiles, we selected 15c for in vivo
efficacy studies. In a sheep model, compound 15c blocked late
airway response (LAR) and airway hyperresponsiveness
(AHR) after i.v. infusion at 1 mpk.24 It also displayed good
efficacy on BAL cells/pulmonary function from ovalbumin
sensitized and challenged Brown Norway rats at 3, 10, and 30
mpk oral dosing (Table 8). With these favorable profiles,
compound 15c was selected as a preclinical candidate (MK-
8318) for further development.
Scheme 1. Representative synthetic process for the prepara-
tion of tetrahydroquinolines as CRTh2 antagonist.a
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aConditions: a. Zn, 4-fluoroaniline, acetic acid/water, 80 oC 100%;
NaOH (5N), dioxane, 100%. b. Eaton's reagent, 70 oC, 40%; Boc2O, NEt3,
DMAP, dioxane, 58%. c. titanium (IV) ethoxide, cyclopropylamine, THF,
then NaBH4, CH2Cl2/MeOH, 90%. d. Ethyl 4-chloro-4-oxobutanoate,
Hunig’s base, dioxane, 90%. e. TFA, CH2Cl2, 96%; 4-Trifluoromethoxy
benzoyl chloride, NEt3, DMAP, CH2Cl2, 87%. f. NaOH (1 N),
THF/MeOH, 91%.
Table 7. Pharmacokinetics of 15c in preclinical species.
In conclusion, a novel series of tricyclic tetrahydroquino-
lines were identified as potent and selective CRTh2 antago-
nists employing literature based drug design. The agonism and
antagonism switch was achieved through structure based drug
design (SBDD) using a CRTh2 receptor homolog model. A
systematic SAR study was carried out and the key pharmaco-
phores were quickly identified to guide the SAR effort. The
challenge of poor exposure seen in rat was overcome by dos-
ing a number of compounds orally and metabolite ID studies
through focused SAR studies on the middle tricyclic core. A
balance between rational drug design and extensive SAR study
resulted in the identification of compound 15c as a potent
CRTh2 receptor antagonist with good in vitro and in vivo ac-
tivity. This compound was selected as a preclinical candidate
(MK-8318) due to its favorable PK profile suitable for once
daily oral dosing and clean ancillary profiles. The detailed
pharmacological and clinical evaluation of 15c as a potential
treatment of asthma will be reported in due courses.
Table 8. Effect of compound 15c with oral dosing on re-
coverable BAL cells from ovalbumin sensitized and chal-
lenged Brown Norway rats.a
aThe effect of 15c (3 - 30 m/kg, p.o.; QD for 3 days) on differential
BAL recoverable inflammatory cells measured 24 hr post antigen (oval-
bumin 1%; 30 min) challenge. p<0.05 compared to negative and positive
control.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Biological protocol, in vitro activity profile and ancillary profiles
of compound 15c, in vivo metabolism of 15c, homology modeling
of CRTh2 receptor, representative experimental procedures, NMR
and MS data for key compounds. (PDF)
The typical synthetic scheme for the preparation of the tet-
rahydroquinoline analogs is illustrated in Scheme 1. The syn-
thesis started from ethyl 2-oxocyclopentanecarboxylate 17. It
was treated with 4-fluoroaniline in the presence of Zn to give
an aminoester which was hydrolyzed to acid 18. The acid was
converted to ketone 19 upon treatment with Eaton’s reagent25
followed by Boc protection. At this stage the racemic interme-
diate 19 was resolved with chiral SFC to provide enantiomeri-
cally pure isomer. The cyclopropyl amine was introduced
through reductive amination to give compound 20 which was
acylated resulting in amide 21. The Boc moiety was removed
with TFA and the intermediate was coupled with 4-
trifluoromethoxy benzoyl chloride to give compound 22 which
AUTHOR INFORMATION
Corresponding Author
* Tel.: +1 9087403734. E-mail address:
xianhai.huang@merck.com (X. Huang). Tel.: +1 9087404733. E-
mail address: anandan.palani@merck.com (A. Palani).
ACS Paragon Plus Environment

Page 7 of 8
ACS Medicinal Chemistry Letters
(13) Norman P. Update on the Status of DP2 Receptor Antagonists;
from Proof of Concept Through Clinical Failures to Promising New
Drugs. Expert Opin. Investig. Drugs 2014, 23, 55-66.
(14) Pettipher, R.; Whittaker, M. Update on the Development of
Antagonists of Chemoattractant Receptor-Homologous Molecule
Expressed on Th2 Cells (CRTH2). From Lead Optimization to Clini-
cal Proof-of-Concept in Asthma and Allergic Rhinitis. J. Med. Chem.
2012, 55, 2915−2931. And references cited therein.
(15) Norman, P. Indole-based CRTH2 Antagonists, Expert Opin.
Ther. Patents 2005, 15, 1817-1823.
(16) Ulven, T.; Kostenis, E. Novel CRTh2 Antagonists: a Review
of Patents from 2006 to 2009, Expert Opin. Ther. Patents 2010, 20,
1505-1530.
(17) Lamers, C.; Flesch, D.; Schubert-Zsilavecz, M.; Merk, D.
Novel Prostaglandin Receptor Modulators: a Patent Review (2002-
2012) - part I: non-EP Receptor Modulators. Expert Opin. Ther. Pa-
tents 2013, 23, 47-77.
(18) Gallant, M.; Beaulieu, C.; Berthelette, C.; Colucci, J.;
Crackower, M. A.; Dalton, C.; Denis, D.; Ducharme, Y.; Friesen, R.
W.; Guay, D.; Gervais, F. G.; Hamel, M.; Houle, R.; Krawczyk, C.
M.; Kosjek, B.; Lau, S.; Leblanc, Y.; Lee, E. E.; Levesque, J.-F.;
Mellon, C.; Molinaro, C.; Mullet, W.; O’Neill, G. P.; O’Shea, P.;
Sawyer, N.; Sillaots, S.; Simard, D.; Slipetz, D.; Stocco, R.; Sørensen,
D.; Truong, V. L.; Wong, E.; Wud, J.; Zaghdane, H.; Wang, Z. Dis-
covery of MK-7246, a Selective CRTh2 Antagonist for the Treatment
of Respiratory Diseases. Bioorg. Med. Chem. Lett. 2011, 21, 288-293.
(19) Xiao, D.; Zhu, Z.; Yu, Y.; Shao, N.; Wu, J.; McCormick, K.
D.; Dhondi, P.; Qin, J.; Mazzola, R.; Tang, H.; Rao, A.; Siliphaivanh,
P.; Qiu, H.; Yang, X.; Rivelli, M.; Garlisi, C. G.; Eckel, S.; Mukho-
padhyay, G.; Correll, C.; Rindgen, D.; Aslanian, R.; Palani, A. Quali-
ty by Design (QbD) of Amide Isosteres: 5,5-Disubstituted Isoxa-
zolines as Potent CRTh2 Antagonists with Favorable Pharmacokinetic
and Drug-like Properties. Bioorg. Med. Chem. Lett. 2014, 24, 1615-
1620.
(20) Liu, J.; Wang, Y.; Sun, Y.; Marshall, D.; Miao, S.; Tonn, G.;
Anders, P.; Tocker, J.; Tang, H. L.; Medina, J. Tetrahydroquinoline
Derivatives as CRTh2 Antagonists. Bioorg. Med. Chem. Lett. 2009,
19, 6840–6844.
(21) Luker T.; Bonnert R.; Schmidt J.; Sargent C.; Paine S. W.;
Thom S.; Pairaudeau G.; Patel A.; Mohammed R.; Akam E.; Dougall
I.; Davis A. M.; Abbott P.; Brough S.; Millichip I.; McInally, T.
Switching between Agonists and Antagonists at CRTh2 in a Series of
Highly Potent and Selective Biaryl Phenoxyacetic Acids, Bioorg.
Med. Chem. Lett. 2011, 21, 3616–3621.
Author Contributions
1
2
3
4
5
6
7
8
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the manu-
script.
ACKNOWLEDGMENT
We thank Dr. Eric Meade for his help editing the manuscript, Dr.
Hong Mei for helpful discussion, the MS and NMR groups for
spectroscopic data, and Drs. William Greenlee and Joseph Vacca
for support of the program.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ABBREVIATIONS
CRTh2, chemoattractant receptor homologous molecule ex-
pressed on T-Helper type 2; SBDD, structure based drug design;
ICS, inhaled corticosteroids; SABAs, short-acting beta agonists;
LABAs, long-acting beta agonists; LAMAs, long-acting musca-
rinic antagonists; FDCs, fixed-dose combinations; DP2, Prosta-
glandin D2 receptor 2; TP receptor, thromboxane A2-prostanoid
receptor; PGD2, prostaglandin D2; MRL, Merck Research Labor-
atory; cAMP, cyclic adenosine monophosphate; SAR, structure-
activity relationship; PK, pharmacokinetics; AUC, area under
curve; TDI, time-dependent inhibition; PXR, pregnane X recep-
tor; LAR, late airway response; AHR, airway hyperresponsive-
ness; TFA, trifluoroacetic acid.
REFERENCES
(1) The Global Asthma Network, The Global Asthma Report 2014.
(2) Braman, S. S. The Global Burden of Asthma. Chest 2006, 130,
4S-12S.
(3) Xia, Y.; Kelton, C. M. L.; Xue, L.; Guo, J. J.; Bian, B.; Wigle,
P. R. Safety of Long-acting beta Agonists and Inhaled Corticosteroids
in Children and Adolescents with Asthma, Ther. Adv. Drug Saf. 2013,
4, 254–263.
(4) Kew K. M.; Dahri K.; Long-acting Muscarinic Antagonists
(LAMA) Added to Combination Long-acting beta2-agonists and
Inhaled Corticosteroids (LABA/ICS) versus LABA/ICS for Adults
with Asthma. Cochrane Database Syst. Rev. 2016, Jan 21,
(1):CD011721.
(5) Mohit Nasa, Management of Severe Asthma: A Transition from
Inhalations to Biologics. Immune and Inflammatory, Decision Re-
sources Group Report, November 16, 2016;
(6) Barnes, P. J. Drugs for Asthma. Br. J. Pharmacol. 2006, 147,
S297-S303.
(7) Chen, J.; Budelsky, A.; Prostaglandin D2 Receptor CRTH2 An-
tagonists for the Treatment of Inflammatory Diseases, Prog. Med.
Chem. – Vol. 50, Elsevier B.V.; Edited by Lawton, G.; Witty, D. R.
2011, 49-107. And references cited therein.
(8) There were about 60 discovery research publications from the
pharmaceutical industry. We apologize that these were not cited here
due to space limit.
(9) Schuligoi, R.; Sturm, E.; Luschnig, P.; Konya, V.; Philipose, S.;
Sedej, M.; Waldhoer, M.; Peskar, B. A.; Heinemann, A. CRTh2 and
D-type Prostanoid Receptor Antagonists as Novel Therapeutic Agents
for Inflammatory Diseases. Pharmacology 2010, 85, 372-382.
(10) Pettipher, R.; Hansel, T. T. Antagonists of the Prostaglandin
D2 Receptor CRTh2. Prog. Respir. Res. 2010, 39, 193-200.
(11) Xue, L.; Salimi, M.; Panse, I.; Mjösberg, J. M.; McKenzie, A.
N.; Spits, H.; Klenerman, P.; Ogg, G. Prostaglandin D2 activates
group 2 innate lymphoid cells through chemoattractant receptor-
homologous molecule expressed on TH2 cells. J. Allergy Clin. Immu-
nol. 2014, 133, 1184-1194.
(12) Sugimoto H, Shichijo M.; Iino T.; Manabe Y.; Watanabe A.;
Shimazaki M.; Gantner F.; Bacon K. B. An Orally Bioavailable Small
Molecule Antagonist of CRTh2, Ramatroban (BAY u3405), Inhibits
Prostaglandin D2-induced Eosinophil Migration in vitro. J. Pharma-
col. Exp. Ther. 2003, 305, 347-352.
(22) Hirai, H.; Tanaka, K.; Takano, S.; Ichimasa, M.; Nakamura,
M.; Nagata, K. Cutting Edge: Agonistic Effect of Indomethacin on a
Prostaglandin D2 Receptor, CRTh2. J. Immunol. 2002, 168, 981-985.
(23) Cox K. A.; Dunn-Meynell K.; Korfmacher W.; Broske L.;
Nomeir A. A.; Lin C. C.; Cayen M. N.; Barr W. H. Novel in vivo
Procedure for Rapid Pharmacokinetic Screening of Discovery Com-
pounds in Rats. Drug Discov. Today 1999, 4, 232-237.
(24) Smith N.; Broadley, K. J. Optimisation of the Sensitisation
Conditions for an Ovalbumin Challenge Model of Asthma. Int. Im-
munopharmacol. 2007, 7, 183–190.
(25) Eaton, P. E.; Carlson, G. R.; Lee, J. T. Phosphorus Pentoxide-
methanesulfonic Acid. Convenient Alternative to Polyphosphoric
Acid. J. Org. Chem. 1973, 38, 4071-4073.
ACS Paragon Plus Environment

ACS Medicinal Chemistry Letters
Page 8 of 8
Table of Contents
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
ACS Paragon Plus Environment

Page 9 of 8
ACS Medicinal Chemistry Letters
1
2
3
4
Graphic of contents
5
6
Discovery of MK-8318, a Potent and Selective CRTh2 Receptor Antagonist for the
7
8
Treatment of Asthma†
9
Xianhai Huang,1,* Jason Brubaker2 Wei Zhou,1 Purakkattle J. Biju,1 Li Xiao,1 Ning Shao,1 Ying
Huang,1 Li Dong,1 Zhidan Liu,1 Rema Bitar,1 Alexei Buevich,1 Joon Jung,2 Scott L. Peterson,2
John W. Butcher,2 Joshua Close,2 Michelle Martinez,2 Rachel N. MacCoss,2 Hongjun Zhang,2
Scott Crawford,2 Kevin D. McCormick,1 Robert Aslanian,1 Ravi Nargund,1 Craig Correll,3
Francois Gervais,3 Hongchen Qiu,4 Xiaoxin Yang,4 Charles Garlisi,4 Diane Rindgen,5 Kevin M.
Maloney,6 Phieng Siliphaivanh,2 and Anandan Palani1,*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment