Use of libraries to access new chemical space: Applications to CRTH2

Article abstract of DOI:10.1016/j.bmcl.2012.04.041

The generation of novel CRTH2 ligands in heavily congested chemical space, by de novo design of libraries is disclosed. Novel (1719) compounds across seven libraries were synthesised. More than 100 of these compounds showed binding potency <3 μM against CRTH2, with the most potent being 247 nM. These libraries produced novel series and demonstrated that this approach is a viable one.

Full text of DOI:10.1016/j.bmcl.2012.04.041

Bioorganic & Medicinal Chemistry Letters 22 (2012) 3682–3687
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Use of libraries to access new chemical space: Applications to CRTH2
⇑
M. Abid Masood , Mark Gardner, Kevin Dack, David Winpenny, Graham Lunn
Pfizer Worldwide Medicinal Chemistry, Sandwich Laboratories, Ramsgate Road, Sandwich CT13 9NJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The generation of novel CRTH2 ligands in heavily congested chemical space, by de novo design of libraries
is disclosed. Novel (1719) compounds across seven libraries were synthesised. More than 100 of these
Received 12 July 2011
Revised 6 April 2012
Accepted 7 April 2012
Available online 20 April 2012
compounds showed binding potency <3
lM against CRTH2, with the most potent being 247 nM. These
libraries produced novel series and demonstrated that this approach is a viable one.
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
Keywords:
Prostanoid
Prostaglandin
CRTH2
Antagonist
Libraries
PGD2 is an arachadonic acid-derived prostaglandin1 produced
in large quantities when asthmatic lung tissues are challenged by
allergens. PGD2 contracts the airway tissue as well as stimulating
an inflammatory response.2
O
O
O
OH
OH
O
X
O
X
N
OH
N
Y
OH
z
PGD2 was also found to be the ligand for a second receptor, DP2
(originally known as CRTH2). Chemoattractant receptor homolo-
gous molecule expressed on TH2 lymphocytes (CRTH2) are acti-
vated by PGD2 and a range of responses such as chemotaxis and
mediator release are triggered. These findings have resulted in con-
siderable interest in the development of CRTH2 antagonists as
treatments for asthma and allergic rhinitis.
R
N
4
R
1
2
3
R
Indoleacetic Acids
>27 patents
(X,Y,Z can be C,N or O)
Phenoxyacetic Acids
5 patents
heterocyclic Acids
3 patents
X can be C
O
S
H
N
CO2H
O
O
The structures of some known CRTH2 antagonists3 and exam-
ples of generic structures that have been patented are shown in
Figure 1.
N
F
N
6
5
O
Cl
HO2C
Ramatroban
Indomethacin
The non-selective cyclooxygenase (COX) inhibitor indometha-
cin 5, is also a potent CRTH2 agonist,4 whereas the thomboxane
receptor antagonist Ramatroban 6 is a CRTH2 antagonist.5
As part of Pfizer’s effort towards discovering a novel CRTH2
antagonist, an analysis of the CRTH2 ligand patent literature (>60
patents) revealed the common motif/pharmacophore to be an aryl
group attached to a carboxylic acid.6
In-silico analysis of the Pfizer screening compound collection
was carried out to identify the number and structures of the car-
boxylic acids it contained. On comparison of these structures with
the known chemical space for prostanoid ligands, it was apparent
that novel acids sharing some related chemical features were
under-represented and consequently finding novel chemical space
Figure 1. Examples of CRTH2 ligands.
with activity for CRTH2 from the compound file or commercial
compound collections would be difficult.
Libraries were therefore designed with the goal of delineating
new chemical space for these prostanoid targets. In addition,
screening a set of specifically designed library compounds against
prostanoid targets would likely give an improved hit rate as com-
pared to a less targeted, very resource intensive HTS.
Ulven et al.7 used a pharmacophore model based on the genetic
similarity of CRTH2 to the AT1 and AT2 receptors for in-silico
screening to identify leads from commercial compound collections,
and Frimurer et al. generated a pharmacophore model of the core
ligand-binding site generated using the known crystal structure
of bovine Rhodopsin combined with data on mutagenesis and
⇑
Corresponding author. Tel.: +44 07709241982.
E-mail address: mabidmasood@gmail.com (M. Abid Masood).
0960-894X/$ - see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.04.041

M. Abid Masood et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3682–3687
3683
SAR from known ligands for 7TM receptor proteins (GPCRs) to the
same end. Both these approaches successfully identified leads from
commercial libraries which led to development candidates but
were very resource intensive and in a heavily patented arena
may not have delivered novel chemical leads.
Our strategy was to first explore some new synthetic routes to
add to our synthetic protocols and then to design libraries accord-
ing to the following criteria:
ꢀ The final compounds to be carboxylic acids; a key feature of
most prostanoid ligands.
ꢀ Inclusion of key H-bond acceptor and lipophilic motifs and
aromatic scaffold.
Figure 3. Minimized structure of Laropripant.
ꢀ Compounds to be out of the scope of current patents of known
CRTH2 antagonists.
ꢀ Good 3D topology comparison between new and known ligands.
O
O
ꢀ Molecular weight <450.
ꢀ Majority of compounds with clogD7.48 between ꢁ0.5 and 1.5, so
as to maximise the probability of having selective, safe orally
absorbed acids.
i, ii
O
OH
7
OH
N
N
B
+
OH
N
N
ꢀ Libraries should differ in terms of chemistry (e.g., with different
functionalities to maximise diversity) but still be amenable to
rapid prosecution.
Br
R
15
R
O
O
N
Based on these criteria, the following core templates were se-
lected and libraries designed around them (Fig. 2).
O
OH
OH
i, ii
N
N
B
The virtual library compounds were overlayed with a set of
known CRTH2 ligands. Of these Laropripant, a known CRTH2
antagonist was found to have the fewest conformations (Fig. 3),
and this compound was overlayed with each template and used
to help filter down the number of library templates and final
library sizes.
+
N
OH
Br
R
16
8
Kitphos Ligand
P(CycHex)2
R
O
O
17
In all the libraries, the carboxylic acids were protected as tert-
butyl esters so that final stage deprotection could be performed
using a strong acid.
Scheme 1. Reagents and conditions: (i) Pd(OAc)2 (5 mol %), Kitphos 17, K3PO4,
toluene, 100oC, 14 h; (ii) trifluoroacetic acid, dichloromethane, rt, 40 min.
Phenoxyacetic acids are a commonly reported pharmacophore
for CRTH2 ligands9 and this structural feature was conserved in
the majority of the library templates.
tert-butyl ester was carried by treatment with trifluoroacetic acid
at room temperature for 18 h to give the carboxylic acid products
7 and 8. Although Novartis had previously investigated N-alkylated
pyrroles as CRTH2 ligands;12 the templates described in this com-
munication have not been reported.
Library 1: The first library attempted utilised the Suzuki cross
coupling of aryl boronic acids with the heteroaryl bromide tem-
plates 15 and 16, which were made by alkylation of bromoimidaz-
ole and bromopyrazole with tert-butyl bromoacetate. Alkylation
was carried out in quantitative yield by stirring with cesium
carbonate in dimethyformamide (DMF) at room temperature over-
night. The Suzuki cross coupling reactions were carried out under
optimised conditions using Buchwald’s ortho-methoxy-Kitphos li-
gand10 17 and palladium acetate in toluene at 100 °C with potas-
sium phosphate as the base (Scheme 1). Deprotection of the
The library synthesis was carried out on 120
combined success rate11 of 60% was obtained with all compounds
being isolated in >3 mol yield and 85% or greater purity (as deter-
lmol scale and a
l
mined by UV and ELSD).
Library 2: This library series was structurally most similar to
known CRTH2 ligands, but was still outside known CRTH2 chemi-
cal space. The library template was synthesised from commercially
available salicaldehyde 18. Alkylation of 18 with tert-butyl bromo-
acetate in DMF using potassium carbonate at rt for 3 h gave the
alkylated aldehyde in quantitative yield. Reduction of the aldehyde
with sodium borohydride in ethanol and then treatment with car-
bon tetrabromide and triphenylphosphine gave the bromomethyl
compound 19 in a combined 78% yield. This substituted benzyl
bromide 19 was heated with a series of phenols using potassium
carbonate in acetonitrile at 60 °C for 6 h (Scheme 2). In this library,
hydrolysis of the tert-butyl ester was performed using base, be-
cause a cleaner impurity profile resulted than with acidic deprotec-
tion. The success rate of the library, after purification, was 64% with
a purity of >85% as determined by ELSD and UV/vis.
O
O
N
O
N
N
OH
O
OH
R1
OH
N
N
N
O
O
N
O
R1
R1
9
10
8
OH
7
Ar
O
O
N
O
R'
OH
OH
OH
N
R
N
N
R
R
N
N
O
N
N
O
O
N
Library 3: A search of the Pfizer monomer collection revealed
the availability of a commercial compound, Spinaceamine 20.
Alkylation of the imidazole was readily achieved after protection
of the amine to give the carboxylic acid motif and then acylation
to give the diversity.13
R1
R
H
R1
13
R1
14
11
12
Figure 2. Library templates.

3684
M. Abid Masood et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3682–3687
O
O
O
O
O
OH
i, ii, iii
O
OH
i
O
R1
R
R
+
R
+
O
H
NHNH
R
O
2
O
R
Br
19
18
24
25
26
ii
iv, v
OH R
N
O
iii, iv
R1
R
O
R
O
O
R1
R
OH
O
N
N
N
9
O
27
11
Ar
Scheme 4. Reagents and conditions: (i) BrCH2CO2Me, K2CO3, acetone, 0 °C-rt 6 h;
(ii) ethanol, 70 °C, 14 h; (iii) NaOH (1 M aqueous), methanol; (iv) HCl in dioxane, rt
2 h.
Scheme 2. Reagents and Conditions: (i) BrCH2CO2Me, K2CO3, DMF, rt 14 h; (ii)
NaBH4, ethanol, 0 °C, 4 h; (iii) CBr4, PPh3, THF, rt 3 h; (iv) K2CO3, CH3CN, 60 °C, 16 h;
(v) NaOH (1 M), MeOH/THF (4:1), rt, 4 h.
O
O
O
O
O
i
O
Cbz
R
O
R
N
N
R
N
N
R
i
ii
N
HN
BnO
N
N
H
N
H
28
29
O
Spineacamine
20
(quant)
21
22
(+ Regioisomer)
ii
O
(89%)
OH R
R
iii
O
R
R
R1
O
O
N
N
NH
iii
N
30
O
12
HO
R1
iv, v
N
N
N
R1
N
HN
+
Scheme 5. Reagents and conditions: (i) BrCH2CO2Me, Cs2CO3, DMF, rt 14 h; (ii)
NH2NH2, EtOH, 80 °C, 19 h; (iii) alkyl bromide, NaH, DMF, 0 °C to rt (for 2° alkyl
halides); Cs2CO3, THF, 30 °C, 48 h (for 1° alkyl halides), 8 h; (iv) trifluoroacetic acid,
MeCN, rt 14 h.
O
N
O
O
10
23
OH
O
(+ Regioisomer)
O
O
Scheme 3. Reagents and conditions: (i) Benzylchloroformate, dichloromethane,
Hünig’s base, rt, 16 h; (ii) BrCH2CO2Me, Cs2CO3, DMF, rt 13 h; (iii) Pd/C (20 mol %),
EtOH, NH4OAc, 50 °C, 4 h; (iv) HATU, CH3CN, Et3N, DMF; (v) trifluoroacetic acid,
dichloromethane, rt, 8 h.
OH
i, ii
Br
R1
31
O
N
+
N
N
14
32
R1
Spinaceamine 20 was protected as the benzyl carbamate (Cbz)
compound 21 in quantitative yield by reaction with benzyl chloro-
formate in dichloromethane and Hünig’s base at room tempera-
ture, overnight. Deprotonation of the imidazole nitrogen with
sodium hydride in tetrahydrofuran (THF) at 0 °C and then alkyl-
ation with tert-butyl bromoacetate gave approximately a 1:1 mix-
ture of regioisomers 22 in a combined 89% yield (Scheme 3).
The two regioisomers 22 were separated by column chromatog-
raphy and the Cbz group was then removed by phase transfer
hydrogenation using catalytic Pd/C in refluxing ethanol for 4 h.
Both regioisomers of the alkylated spinaceamine 23 were used as
templates in the library to add diversity. The library synthesis
consisted of an amide coupling using HATU (O-(7-aza-
benzotriazol-1-yl)-N,N,N0,N0-tetra-methyluronium hexafluorophos-
phate) in acetonitrile at room temperature. Trifluoroacetic acid
(TFA) mediated deprotection of the tert-butyl ester gave the final
carboxylic acids 10. After purification a library success rate of
69% was obtained with purities of >85% as determined by ELSD
and UV.
Scheme 6. Reagents and conditions: (i) NaN3, CuSO4ꢂ5H2O (20 mol %), DMSO, rt
12 h; (ii) trifluroacetic acid, dichloroethane, rt 8 h.
O
O
i
O
O
ii
H
N
H2N
N
H
O
N
H
O
O
33
34
R1
iii
OH
O
O
O
R1
O
O
R1
N
N
N
N
14
35
Scheme 7. Reagents and conditions: (i) HATU, Et3N, R1CO2H, dichloromethane,
30 °C, 16 h; (ii) CBr4, PS-PPh3, dichloromethane, 0 °C, 2 h; (iii) trifluoroacetic acid,
dioxane, 30 °C, 3 h, rt.
Library 4: The design of this library was based on a functional-
ised pyrazole template 11. Alkylation of a 1,3-diketone with an
alkyl halide using potassium carbonate in acetone at room temper-
ature for 6 h gave the alkylated diketone 25. This was not isolated
but used directly in the next step (Scheme 4).
Cyclisation of the diketone intermediate 25 with the commer-
cially available tert-butyl hydrazinoacetate 26 by heating in

M. Abid Masood et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3682–3687
3685
Table 2
Table 1
Summary of hCRTH2 binding and functional data for most potent library compounds
Summary of biological data for library compounds by series
R/compound
hCRTH2 binding Kia (nM)
Number Compound structure
Number of
compounds
made (%
Number of
compounds with
>40% inhibition at
Br
success rate)
2.8 lM
N
36
37
563
N
O
O
N
O
OH
OH
O
N
7,8
129 (60)
529 (64)
4
N
N
R1
R1
O
574
O
N
OH
N
9
105
O
O
O
Ar
Cl
O
N
N
R1
N
Cl
10
529 (69)
0
N
38
623
N
O
O
OH
O
R'
O
O
N
R
N
R
N
N
11
12
148 (87)
89 (36)
0
5
O
HO
39
631
O
N
OH
N
R
R1
R
O
O
O
OH
OH
N
40
752
13
24
145 (31)
150 (67)
16
N
N
O
N
S
N
N
O
R1
O
O
O
Cl
O
0
N
N
41
247
N
O
R1
O
N
O
O
ethanol at 70 °C overnight gave the pyrazole products 27. Base
mediated ester hydrolysis with sodium hydroxide gave, after
work-up, the carboxylic acids 11 with an overall success rate of
36%. The majority of compounds lost in this library were at the
pyrazole cyclisation and/or ester hydrolysis steps (33%).14 At-
tempts at acid mediated ester deprotection gave complex mixtures
and so base hydrolysis was used on these particular templates.
Library 5: Alkylation of the 1,3-diketo ester 30 with tert-butyl
bromoacetate and then cyclisation with hydrazine in ethanol at
80 °C for 19 h gave the pyrazole templates 30 in >60% yields. This
was the basis of the route for the fifth library, again using a pyra-
zole core (Scheme 5).
N-alkylation of the pyrazole templates 35 was carried out using
one of two sets of conditions depending on whether primary or
secondary alkyl halides were used. For primary halides, alkylation
was effected by stirring with cesium carbonate in tetrahydrofuran
(THF) at room temperature for 48 h. For secondary halides, the pyr-
azoles 35 were deprotonated using sodium hydride in dimethyfor-
mamide (DMF) at 0 °C, followed by addition of the alkyl halide and
left stirring at 30 °C for 8 h. This gave, after deprotection and
O
O
42
333
O
N
O
O
O
O
43
44
492
O
N
O
Cl
O
520
O
(continued on next page)

3686
M. Abid Masood et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3682–3687
in dichloromethane at 0 °C for 2 hours. Yields in the route valida-
Table 2 (continued)
tion work were in the 40-88% range. During the final acid-medi-
ated deprotection of the tert-butyl esters 35, decarboxylation of
the product acids was sometimes seen, this being the major reason
for the low library success rate of 31%.
In total, across all the libraries, >1700 compounds were syn-
thesised with an average library success rate of 59%, an excellent
success rate considering the diversity of the chemistry.
Biological activity against human CRTH2 was determined in a
R/compound
hCRTH2 binding Kia (nM)
O
O
F
O
45
591
O
a
The Cheng and Prussof relationship uses the IC50s determined by SiGHTS in
single point binding assay at 2.8 lM. The Ki values were deter-
conjunction with the KD and ligand concentration supplied by the analyser to cal-
culate the Ki. Ki are the geometric mean of three or more independent
determinations.
mined for 130 (7.5% of total library set) active compounds showing
>40% inhibition17 (Table 1).
Full dose response screening yielded 10 compounds with
Ki<1 lM (Table 2). Thus, novel series were identified with poten-
cies which ranged from 247 to 752 nM.
While the potency of these compounds is still modest, new
leads distributed in three distinct classes were identified.
The goal of the project was to design potent compound libraries
which had some features present in known CRTH2 ligands, but that
were sufficiently different to be clearly outside the patent scope of
known ligands and have improved physicochemical properties.
The molecular weight versus clogP plot shown in Figure 4 illus-
trates that the known CRTH2 ligands are quite large and lipophilic,
a particular problem since they are also acidic. In contrast the de-
signed library and active library compounds are generally smaller
and less lipophilic suggesting that they may constitute better start-
ing points for the discovery of orally active CRTH2 inhibitors.
The libraries described thus gave rapid access to novel lead
CRTH2 ligands despite the backdrop of congested prior art demon-
strating the power of parallel synthesis. Even though the probabil-
ity of any one of these compounds being active was relatively low,
the efficiency of parallel synthesis made the cost/benefit ratio of
this experiment desirable and resulted in the identification of no-
vel series for further lead optimisation.
Acknowledgements
The authors would like to thank Nunzio Sciammetta, Charles
Mowbray, Thomas Rykmans, James Crawforth and Andy Bell for
their valuable suggestions in the preparation of this communica-
tion. The authors are also greatly indebted to the Separation and
Structural Sciences group, the Department of Pharmacokinetics,
Dynamics and Metabolism and the High Throughput Screening
Group at Pfizer for their efforts in this project.
Figure 4. A molecular weight versus clogP plot of known CRTH2 ligands and library
compounds.
purification, an excellent library success rate of 87% (>85% purity).
As the pyrazoles 30 have a plane of symmetry, alkylation on either
nitrogen gave the same product.
Library 6: This library was synthesised by a one-pot three-com-
ponent coupling reaction utilising copper(I)-catalysed triazole for-
mation chemistry. In-situ reduction of copper(II) to copper(I) by
DMSO catalyses the reaction.15 Commercially available tert-butyl-
but-3-ynoate 37 was reacted with sodium azide and a series of al-
kyl and benzyl halides 36 and the resulting compounds purified
using preparative HPLC. Acid mediated deprotection afforded the
disubstituted triazole-carboxylic acids 14 with a success rate of
67%. The final compounds were isolated in >85% purity as deter-
mined by ELSD and UV (Scheme 6).
Library 7: In order to increase diversity in both structure and in
the chemistry, a library was designed in which an oxadiazole 14
was formed by the coupling of two carboxylic acid groups16
(Scheme 7).
Acyl hydrazide 33 was first coupled with a set of carboxylic
acids to give the unsymmetrical diacyl hydrazides 34. Initial at-
tempts at cyclisation to the desired oxadiazoles 35 were hampered
by low yields, in addition to triphenylphosphine oxide residue con-
tamination of the products after purfication. Optimised conditions
were subsequently developed which utilised polymer-supported
triphenylphosphine (typically 10 equiv) and carbon tetrabromide
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.04.
041.
References and notes
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sufficient quantity and purity) divided by the number of library compounds
attempted.
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17. CRTH2 binding assay: See Appendix 2