Quality by design (QbD) of amide isosteres: 5,5-Disubstituted isoxazolines as potent CRTh2 antagonists with favorable pharmacokinetic and drug-like properties

Article abstract of DOI:10.1016/j.bmcl.2014.01.043

Isoxazoles are frequently used amide isosteres, as shown in the context of discovery of CRTh₂ antagonists from amide 1 to isoxazole 2. However, persistent agonism and poor solubility in isoxazole series presented challenges to its further devel

Full text of DOI:10.1016/j.bmcl.2014.01.043

Bioorganic & Medicinal Chemistry Letters 24 (2014) 1615–1620
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Quality by design (QbD) of amide isosteres: 5,5-Disubstituted
isoxazolines as potent CRTh2 antagonists with favorable
pharmacokinetic and drug-like properties
a
a
a
a
a
a
Dong Xiao a, , Xiaohong Zhu , Younong Yu , Ning Shao , Jie Wu , Kevin D. McCormick , Pawan Dhondi ,
Jun Qin a, Robert Mazzola a, Haiqun Tang a, Ashwin Rao a, Phieng Siliphaivanh b, Hongchen Qiu c,
Xiaoxin Yang c, Maria Rivelli c, Charles G. Garlisi c, Steve Eckel d, Gitali Mukhopadhyay d, Craig Correll d,
Diane Rindgen e, Robert Aslanian a, Anandan Palani a
⇑
a Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
b Discovery Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA
c In vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
d Immunology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
e Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Isoxazoles are frequently used amide isosteres, as shown in the context of discovery of CRTh2 antagonists
from amide 1 to isoxazole 2. However, persistent agonism and poor solubility in isoxazole series pre-
sented challenges to its further development. Based on the concept of quality by design (QbD), 5,5-disub-
stituted isoxazolines 3 were introduced. The chirality at 5 position of isoxazolines controlled the switch
between two modes of actions, which led to a novel series of pure antagonists. This non-planar motif also
conferred a change of shape of these molecules, which avoided flat structures and improved their phys-
ical properties.
Received 18 October 2013
Revised 10 January 2014
Accepted 14 January 2014
Available online 2 February 2014
Keywords:
CRTh2 antagonists
Agonism/antagonism switch
Quality by design (QbD)
Amide isostere
Ó 2014 Elsevier Ltd. All rights reserved.
Isoxazolines
Drug-like properties
The unmet medical needs in the treatment of chronic respira-
tory diseases such as asthma, COPD and allergic rhinitis have
prompted the research and development of CRTh2 receptor antag-
onists as novel therapy.1 CRTh2 (chemoattractant receptor-homol-
ogous molecule expressed on Th2 cells) receptors2 are one of the
two types of G-protein coupled receptors (GPCRs) that mediates
the biological actions of prostaglandin D2 (PGD2).3 PGD2 is a hor-
mone-like metabolite in the arachidonic acid pathway, known to
be involved in allergic inflammation. The CRTh2 receptors are ex-
pressed on eosinophils, basophils, Th2 cells, macrophages and neu-
trophiles.4 It has been shown that the PGD2 induced chemotaxis,
degranulation and cytokine production are exclusively exerted
through CRTh2 receptors. Therefore, modulation of CRTh2 receptors
is postulated to reduce excessive allergic responses and produce
beneficial therapeutic effects.5 In addition, Indomethacin,6 (Fig. 1)
a nonselective inhibitor of COX-1 and COX-2, has demonstrated
an agonist effect on CRTh2 receptors. Ramatroban,7 (Fig. 1) a
thromboxane A2 antagonist, which was approved for allergic rhini-
tis, was thought to have efficacy derived from a moderate CRTh2
activity. These proven pharmacological interventions lent further
credibility to the targeting of CRTh2 receptors for the treatment
of respiratory diseases. The last decade has seen the rapid expan-
sion of small molecule CRTh2 antagonist discovery research, which
has been reviewed extensively.8 Several CRTh2 antagonists have
advanced to clinical trials.1a The Merck team has recently pub-
lished the discovery of MK-7246 that also entered clinical trials9
(Fig. 1).
To fully explore the potential opportunities of CRTh2 antago-
nism therapeutics, a backup medicinal chemistry program was ini-
tiated. At the inception of the program, our focus was drawn to a
screening derivative amide 1 (Fig. 2). These types of compounds
generally demonstrated good CRTh2 potency. The major concern
for this series was the potential amide hydrolysis thought to be
linked to unsatisfactory pharmacokinetic profiles. Therefore, a
number of heterocycle replacements were investigated and the
⇑
Corresponding author. Tel.: +1 9087404484.
E-mail address: dong.xiao@merck.com (D. Xiao).
http://dx.doi.org/10.1016/j.bmcl.2014.01.043
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

1616
D. Xiao et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1615–1620
CO2H
CO2H
CO2H
MeO
N
F
F
N
N
O
N
S
Cl
HN
S
O2
O2
Indomethacin
Ramatroban
MK-7246
Figure 1. Representative CRTh2 modulators.
O
N
O
N
O
R1
R2
N
N
O
CO2H
N
O
CO2H
N
CO2H
N
H
N
N
1
2
3
O
F
F
F
Figure 2. Leads and lead optimization targets.
isoxazole 2 (Ki CRTh2 = 2.6 nM, partial agonist) emerged as a key
lead. Drawbacks of 2 included partial agonist behavior and low
solubility. To address these issues, we consciously applied quality
by design (QbD) principle to the next round of amide replacement
optimization. The QbD concept emphasizes that quality should be
built into a product by design with an understanding of the
product and process by which it is developed and produced.10
QbD is a scientific risk-based, holistic and proactive approach. This
approach seeks to identify and understand the risks involved in
each steps and how best to mitigate these risks.11 The QbD
approach has been implemented by US Food and Drug
Administration (US FDA) in pharmaceutical pre-market processes,
particularly in drug manufacturing.12 This concept has also been
introduced in drug discovery processes as well.13 It was postulated
that, by design-in the druglikeness to discovery-stage analogs and
preclinical candidates, the risk of development failures could be
mitigated and the eventual success rate could be improved.14
Focusing on quality amide bond mimics,15 we envisioned adoption
of 5,5-disubstituted isoxazolines 3 as replacement of amide 1
(Fig. 2). Compared to isoxazole 2, the druglikeness of isoxazolines
3 identified by QbD included steric bulkiness and chiral preference
to influence agonism/antagonism behavior, di-substitutions of
desirable non-flat structures16 that would likely improve solubil-
ity.17 This paper will present the synthesis and pharmacological
and physicochemical characterizations of isoxazoline amide
mimics 3 as potent, selective CRTh2 antagonists with excellent
pharmacokinetic profiles. The successful completion of this study
also demonstrated the importance of QbD concept in discovery
medicinal chemistry.
The synthesis of the isoxazolines 3 started with commercial 4-
bromo-2-aminobenzoic acid. It was treated with excess Et3N and
methyl 6-chloro-6-oxohexanoate followed by 4-fluoroaniline at
80 °C overnight to afford the bromoquinazolinone core 5. Formyla-
tion of the bromide followed by hydroxylamine treatment pro-
vided ample quantity of oxime 6. Subsequent 2+3 cycloaddition
yielded isoxazoline methylesters which were hydrolyzed to pro-
duce the final compounds 3. The entire synthesis was straight-for-
ward and ready to scale up (Scheme 1).
The initial design strategy was to keep one phenyl group as R1
and insert another R2 at the 5 position of the isoxazoline. The first
round of SAR was aimed at securing an optimal R2 group with bal-
anced potency and drug-like properties. The methyl substituted
analog 3a showed comparable CRTh2 binding activity as isoxazole
2 with moderate cAMP antagonism as a racemic mixture. With
increasingly bulkier R2 groups, the analogs 3b–3d, albeit potent
in the binding assay,18 showed reduced cAMP activity,18 and began
to trend toward agonism. With the intention of improving aqueous
solubility, adoption of polar groups such as hydroxymethyl or
methoxymethyl in 3e–3f resulted in decreased CRTh2 binding po-
tency. The diphenyl analog 3g, though marginally potent in the
binding assay, showed weak activity in the cAMP assay. The indane
analog 3h proved to be the most potent in the CRTh2 binding assay,
but decisively an agonist in the cAMP assay. In conclusion, the opti-
mal R2 substitution was the methyl group, which showed both
good CRTh2 and cAMP binding activities (Table 1).
Concentrating efforts on the methyl analogs provided several
advantages. The addition of the methyl group reinforces chiral bias
by analogy of the Thorpe–Ingold effect.19 This methyl would also
Cl
CO2Me
2.5 eq.
1)
2)
1) Pd, CO
O
Br
N
O
CO2Me
Br
NH2
OH
Et3SiH
Et3N, 4 eq.
N
2) NH2OH-HCl
NaOAc
O
F
H2N
F
4
5
3 eq.
R1
R2
R2
O
HO
N
N
1)
N
O
CO2H
NaOCl
R1
N
O
CO2Me
N
N
2) LiOH
6
3
F
F
Scheme 1. Synthesis of 5,5-disubstituted isoxazolines.

D. Xiao et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1615–1620
1617
Table 1
CRTh2 activities of 5-phenylisoxazolines
R
N
O
CO2H
N
F
Entry
R
Ki (CRTh2) (nM)
cAMP IC50 (nM)
Entry
R
Ki (CRTh2) (nM)
cAMP IC50 (nM)
O
O
O
N
N
N
Ph
Ph
18.6
Antagonist
58.5
antagonist
3a
4.7
3e
2.5
Me
HO
O
N
Ph
Et
Ph
O
38.7
Antagonist
79.7
antagonist
3b
3c
3d
1.8
1.8
1.6
3f
1.9
MeO
O
N
N
Ph
nPr
Ph
nBu
Ph
Ph
73.4
Antagonist
33.7
antagonist
3g
3h
13.7
1.1
O
O
N
N
Partial agonist
Agonist
Data represented the average values of duplicates or triplicates 18.
Table 2
SAR of 5-methyl-phenylisoxazolines
R
N
O
CO2H
N
F
Entry
R
Ki (CRTh2) (nM)
cAMP IC50 (nM)
Entry
R
Ki (CRTh2) (nM)
cAMP IC50 (nM)
Partial agonist
O
O
N
N
(R)
(S)
8.1
Antagonist
3a-(S)
3.7
3a-(R)
3i-(R)
24.9
O
O
N
N
(R)
(S)
10.2
Antagonist
3i-(S)
3j-(S)
4.1
3.4
6.0
Agonist
F
F
F
F
O
O
N
N
(S)
(R)
7.8
Antagonist
3j-(R)
10.5
Partial agonist
F
F
O
O
N
N
(S)
(R)
10.5
Antagonist
3k-(S)
3l-(S)
2.6
3.0
3k-(R)
3l-(R)
2.0
Agonist
ND
Cl
Cl
O
O
N
N
(S)
(R)
5.2
Antagonist
22.3
NC
NC
Data represented the average values of duplicates or triplicates.
prevent isoxazolines from potential oxidative metabolism of the
benzyl oxime ether. Finally, the quaternary carbon substitution
would break the planar linear aromatic structures to improve
physical properties.12 A number of 5-methylisoxazolines with a
small array of 5-phenyl derivatives were synthesized using the
chemistry shown above (Scheme 1). The enantiomeric mixtures
were separated by chiral HPLC. In each enantiomeric series the or-
der of HPLC elution and their bioassay profiles were consistent.
This ensured straight forward assignment of their absolute
stereochemistry.20
The enantiomerically pure 5,5-disubstituted isoxazolines 3
were generally very potent in the CRTh2 binding assay (Table 2),
particularly in the (S) enantiomeric series. The cAMP data showed
more intriguing results. The (S) enantiomer series 3a-(S), 3i-(S), 3j-
(S), 3k-(S) and 3l-(S) exhibited potent antagonist activity, where
the (R) enantiomers 3a-(R), 3i-(R), 3j-(R), 3k-(R) and 3l-(R) were
partial or full agonists (Table 2). As mentioned earlier, one of the
drawbacks of the isoxazole 2 was its agonism. Similar crossover
of mode of actions has been a problem for other CRTh2 chemo-
types.21 In the methylphenyl disubstituted isoxazolines series,

1618
D. Xiao et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1615–1620
Table 3
SAR of 5-methyl-extended phenyl analogs
R
N
O
CO2H
N
F
Entry
R
Ki (CRTh2) (nM)
cAMP IC50 (nM)
Entry
R
Ki (CRTh2) (nM)
cAMP IC50 (nM)
O
O
N
N
N
N
15.2
Antagonist
13.7
antagonist
(R)
(S)
3m-(R)
7.5
3m-(S)
3n-(R)
7.4
O
O
(S)
(R)
4.7
Antagonist
3n-(S)
3o-(S)
3p-(S)
3.7
2.5
1.9
41.7
18.3
19.6
ND
ND
ND
OH
OH
OH
OH
O
O
N
N
(S)
(R)
5.7
Antagonist
3o-(R)
3p-(R)
O
O
N
N
N
N
(S)
(R)
N
N
N
N
9.7
Antagonist
O
O
O
O
(S)
(R)
17.2
Antagonist
3q-(S)
2.3
3q-(R)
5.6
Agonist
S
S
Data represented the average values of duplicates or triplicates.
Table 4
Representative pharmacokinetic profiles of 5,5-disubstituted isoxazolines
R
N
O
CO2H
N
F
O
O
O
O
O
N
N
N
N
N
(S)
(R)
(R)
(S)
(S)
Entry
OH
3n-( )
OH
3o-(
3m-(
)
R
)
S
S
3a-( )
3a-(
)
S
R
Rat (SD) AUC (0–6 h) 10 mpk, po; nMÁh
16895.0
590.8
2.2/ND/1.5
36390
4.7/23.3/3.1
11180.3
2.0/2.8/<1
31158.1
<1/2.7/0.5
Hepatocyte clearance (ml/min/M cell); r/m/h* 1.0/4.2/0.9
O
O
O
O
O
N
N
N
N
N
(S)
(S)
(S)
(S)
(S)
N
F
O
Entry
F
Cl
3p-(S)
3i-(S)
3k-(S)
F
CN
3j-(S)
3l-(S)
Rat (SD) AUC (0–6 h) 10 mpk, po; nMÁh
6537.7
1670.9
<1/13.4/0.7
3408.8
3.7/17.7/3.6
1083.8
2.6/5.2/0.9
11095.6
<1/5.1/1.3
Hepatocyte clearance (ml/min/M cell); r/m/h* 4.1/11.7/1.8
r/m/h: rat/monkey/human.
*
the chirality provided a clean-cut control of agonism/antagonism
and a facile solution to the problem.
binding assay. The more rigid benzooxazole and benzathiazole
analogs also presented a complex picture. The benzooxazole enan-
tiomer 3p-(S) was potent in CRTh2 binding and cAMP assay, but the
enantiomer 3p-(R) was not in binding assay. On the other hand,
benzothiazole enantiomers 3q-(S) and 3q-(R) were potent in bind-
ing assay, but 3q-(R) followed an earlier trend to be an agonist
(Table 3).
All the in vitro data so far proved that 5,5-disubstituted isoxaz-
olines were good amide mimics as CRTh2 antagonists. Several
analogs with excellent binding potency and pure antagonism
profiles were identified. One of the key compound 3p-(S) was
subjected to additional investigations. This compound showed
Based on the most potent indane analog 3h, the extended phe-
nyl substitutions were further investigated. Analogs such as 3m–
3q were synthesized (Table 3). Unlike the phenyl analogs, the
SAR in the extended series did not provide a clean cut picture.
While both enantiomers of the benzyl analogs 3m-(R) and 3m-
(S) were potent in the CRTh2 binding assay, the cAMP assay con-
firmed that both were antagonists. The hydroxylbenzyl analogs
took another trend. The (S) enantiomers 3n-(S) and 3o-(S) were po-
tent in both CRTh2 binding and cAMP assays as antagonists and the
opposite enantiomers 3n-(R) and 3o-(R) were not potent in CRTh2

D. Xiao et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1615–1620
1619
Table 5
Pharmacokinetic profiles of key compound 3p-(S)
O
N
N
N
O
CO2H
O
N
3p-( )
S
F
Species
AUC
lM h
F (%)
Clearance (ml/min/kg)
Vd(ss) (L/kg)
T0.5 (h)
Rat (wistar) 10 mpk, po
Dog (beagle) 3 mpk, po
Monkey (cyno) 3 mpk, po
335
8.4
15.7
86
56
41
0.87
2.8
3.7
0.21
0.51
0.40
4.9
7.5
8.4
Table 6
Physicochemical properties of representative 5,5-disubstituted isoxazolines
R
N
O
CO2H
N
F
g/ml)
Entry
R
HPLC logD
Soluibility pH 7 (
l
Soluibility FASSIF (
17
lg/ml)
Calculated Papp (10À6 cm/s)
31
O
N
2
1.97
8
Ph
O
N
(S)
3a-(S)
1.91
0.98
170
202
90
26
Ph
Ph
O
1
ND
9.0
N
H
O
N
7
2.00
1.98
1.99
85
54
98
17
32
29
12
Ph
Ph
O
N
(R)
3m-(R)
>200
6
O
N
O
8
N
N
O
N
(S)
3p-(S)
1.81
169
125
13
O
IC50 of 6.8 nM in Eosinophil shape change assay18 in human whole
blood assay.
that 5,5-disubstituted isoxazolines could have excellent pharmaco-
kinetic profiles.
After securing the favorable in vitro biological data, the next
logical step was to assess the pharmacokinetic and ADME proper-
ties of these compounds. Historically there have been two reports
that utilized isoxazolines as amide bond isosteres with very limited
profiling,22 our research provided large numbers of diverse analogs
to present a full picture. The drug-like properties of isoxazoline
compounds were systematically evaluated. These properties would
likely determine the prospective of isoxazolines as drug candidates
(Table 4).
To further assess the drug-like profile of isoxazolines, several
physical properties such as HPLC logD and solubility were mea-
sured experimentally. Apparently, the addition of a methyl group
at the 5-position did not alter the HPLC logD significantly. The dif-
ferences between 2 and 3a-(S), 7 and 3m-(R) and 8 and 3p-(S) were
fairly small. On the other hand, the solubility data of 5-methyl
substituted isoxazolines vis-à-vis the isoxazoles revealed consis-
tently much improved solubility at pH 7 and in FASSIF at pH 6.5.
Particularly noteworthy, for the more rigid analogs, 8 versus
3p-(S) at pH 7, the solubility improved as much as 25fold. A likely
reason is that the quaternary center disrupted planer structure and
The pharmacokinetic (PK) studies23 in Sprague-Dawley (SD)
rats indicated that the isoxazoline compounds generally exhibited
moderate to excellent exposures (Table 4). Interestingly, the more
potent enantiomer 3a-(S) showed much better AUC than 3a-(R). All
compounds had low hepatocyte clearance in multiple species, ex-
cept 3i-(S), 3j-(S), 3k-(S) and 3m-(R) in monkeys, confirming a gen-
eral trend of metabolic stability. Among these analogs, 3p-(S) also
showed good exposure and oral bioavailability in rodents, mon-
keys and dogs (Table 5). Collectively, the data shown demonstrated
p
-stacking force, leading to better solubility.17 What is more inter-
esting, as an amide isostere, was that compound 3a-(S) showed
similar solubility to the corresponding benzylamide 1. The amide,
however, has much lower logD, which may be related to poor
permeability of peptide drugs (Table 1). Indeed, the calculated
Apparent Permeability (Papp) showed amide 1 was nearly threefold
worse than isoxazoline 3a-(S). This demonstrated an additional

1620
D. Xiao et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1615–1620
8. (a) Ulven, T.; Kostenis, E. Expert Opin. Ther. Pat. 2010, 20, 1505; (b) Ly, T. W.;
Bacon, K. B. Expert Opin. Invest. Drugs 2005, 14, 769.
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bond isosteres (Table 6).
9. 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.;
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In summary, a useful strategy of using 5,5-disubstituted isoxaz-
olines as amide isosteres in the CRTh2 antagonist program was pre-
sented. Based on the principles of quality by design (QbD),10–14
several salient features of druglikness were built into isoxazolines.
These included a simple one step synthesis resulting in a single
chiral center, which led to chirally differentiated non-flat
molecules. This chirality was utilized successfully to control the
agonism/antagonism switch. Extensive evaluations of pharmacoki-
netic and physical properties were conducted to assess their
likelihood of being drug candidates. The disubstituted isoxazoline
CRTh2 antagonists were metabolically stable and possessed good
pharmacokinetic profiles. These structures had similar solubility
and possibly better permeability compared to amide 1. Indeed,
when applicable, 5,5-disubstituted isoxazolines could be powerful
isostere replacements of amide bonds. The QbD concept utilized in
this study demonstrated the importance of front-loading druglike-
ness to medicinal chemistry design. This approach should be
widely applicable to the discovery of high quality drug candidates
and eventual human medicines.
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18. For the details of CRTh2 binding and cAMP assays, see: Boyce, C. W.; Degrado, S.
J.; Chen, X.; Qin, J.; Mazzola, R. D.; Yu, Y.; Mccormick, K. D.; Palani, A.; Xiao, D.;
Aslanian, R. G.; Wu, J.; Rao, A. U.; Siliphaivanh, P; Methot, J. L.; Zhang, H.;
Kelley, E. H.; Brown, W. C.; Jiang, Q.; Gauuan, J. P.; Leyhane, A.J.: Biju, P. J.;
Dhondi, P. K. Dong, L.; Fevrier, S.; Huang, X.; Vaccaro, H. M. ‘Quinoxalines and
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20. The absolute stereochemistries of each series were assigned by correlation to
analogs 3n-(S) and 3o-(S), which were derived from relative stereochemistry
determined by NMR analysis using the known (R)- and (S)-chiral centers in
phenylmethylpropenyl alcohols. (R)-Phenylmethylpropenyl alcohol, see: Sato,
I.; Asakura, N.; Iwashita, T. Tetrahedron: Asymmetry 2007, 18, 2638; (S)-
Phenylmethylpropenyl alcohol, see: Jones, S.; Valette, D. Org. Lett. 2009, 11,
5358.
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. Bioorg. Med. Chem. Lett. 2011, 21,
288.
Acknowledgments
The authors thank Drs. William Greenlee and Joseph Vacca for
support of this research program. We would also like to thank
Ms. Nancy Kevin for helpful edition of this manuscript.
References and notes
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