Identification of potent CNS-penetrant thiazolidinones as novel CGRP receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2013.12.089

Calcitonin gene-related peptide (CGRP) has been implicated in acute migraine pathogenesis. In an effort to identify novel CGRP receptor antagonists for the treatment of migraine, we have discovered thiazolidinone 49, a potent (K_i = 30 pM, IC₅₀ = 1 nM), orally bioavailable, CNS-penetrant CGRP antagonist with good pharmacokinetic properties.

Full text of DOI:10.1016/j.bmcl.2013.12.089

Bioorganic & Medicinal Chemistry Letters 24 (2014) 845–849
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Identification of potent CNS-penetrant thiazolidinones as novel CGRP
receptor antagonists
Pramod Joshi a, Corey Anderson a, Hayley Binch a, Sabine Hadida a, Sanghee Yoo b, Danielle Bergeron b,
Caroline Decker c, Ernst terHaar d, Jonathan Moore d, Miguel Garcia-Guzman e, Andreas Termin a,
⇑
a Vertex Pharmaceuticals Inc., Department of Chemistry and Drug Innovation, 11010 Torreyana Road, San Diego, CA 92121, United States
b Vertex Pharmaceuticals Inc., Department of Biology, 11010 Torreyana Road, San Diego, CA 92121, United States
c Vertex Pharmaceuticals Inc., Department of Drug Metabolism and Pharmacokinetics, 11010 Torreyana Road, San Diego, CA 92121, United States
d Vertex Pharmaceuticals Inc., Department of Structural Biology, 130 Waverly Street, Cambridge, MA 02139, United States
e Aspyrian Therapeutics Inc., 11189 Sorrento Valley Rd, San Diego CA 92121, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Calcitonin gene-related peptide (CGRP) has been implicated in acute migraine pathogenesis. In an effort
to identify novel CGRP receptor antagonists for the treatment of migraine, we have discovered thiazolid-
inone 49, a potent (Ki = 30 pM, IC50 = 1 nM), orally bioavailable, CNS-penetrant CGRP antagonist with
good pharmacokinetic properties.
Received 12 November 2013
Revised 18 December 2013
Accepted 19 December 2013
Available online 26 December 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Migraine
CGRP antagonists
Thiazolidinone
CGRP is a 37-amino acid neuropeptide that is expressed and re-
leased by the trigeminal ganglia nerve fibers, and plays a critical
role in migraine.1a CGRP signals through a heteromeric receptor
composed of a G protein-coupled receptor called calcitonin recep-
tor-like receptor (CRLR) and a receptor activity modifying protein
(RAMP1). CGRP is one of the most potent endogenous vasodilators
known.1b Increased levels of CGRP are observed during migraine
attacks and intravenous administration of CGRP can induce
migraines.1c
Br
O
OH
Br
O
N
N
H
HN
O
N
NH2
N
H
O
N
N
N
An early clinical proof of concept study showed that intrave-
nous dosing of BIBN4096 (olcegepant), a potent CGRP receptor
antagonist, was efficacious in alleviating pain during migraine
headaches.1a Olcegepant showed comparable efficacy to triptans,
and showed no serious cardiovascular effects.2 Olcegepant has
poor oral bioavailability (% F < 1), and limited CNS exposure; there-
fore its development was discontinued due to the rapid clearance
and poor physical properties of this high molecular weight (MW
855) peptidic molecule.1a We initiated a program to identify a po-
tent, orally bioavailable, CNS-penetrant CGRP-receptor antagonist
with good physicochemical properties. More recently, Merck3–5
has reported positive Phase III clinical trial data for telcagepant
BIBN4096BS (Olcegepant) MW 855
Figure 1. Structure of olcegepant (BIBN4096).
Table 1
a
Compound
IC50
(lM)
Kib
(lM)
Olcegepant
1
2
0.004 0.063
0.74 0.29
0.37 0.16
0.00001 0.00002
0.282
0.032 0.026
IC50 b-lactamse assay7 (n P 3) with cells treated with CGRP, compound and
a
cAMP antibody and represents cellular inhibition of cAMP production.
b
Ki Binding assay (n P 3) SK-N-MC membrane treated with 125I-CGRP, com-
pound and Ki = IC50/(1 + [radioligand]/Kd) was calculated.6
⇑
Corresponding author.
E-mail addresses: Miguel_Guzman@aspyriantherapeutics.com (M. Garcia-Guz
man), andreas_termin@vrtx.com (A. Termin).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.12.089

846
P. Joshi et al. / Bioorg. Med. Chem. Lett. 24 (2014) 845–849
Table 2
Br
OH
Effect of substitution (R1), on the amine of thiazolidinone ring
Br
OH
Br
Br
O
N
O
X
O
S
N
R1
N
N
N
O
N
O
O
N
N
N
N
H
O
N
H
O
N
H
O
1
a
Compound R1
IC50
(l
M)
Kib
(lM)
3
4
5
6
Methyl
iso-Propyl
Cyclopropyl
Methylcyclopropyl
Butyl
4.47 3.23
1.5 1.15
5.15
0.84 0.08
0.32 0.033 0.064
0.203
O
S
0.115 0.011
0.865 0.416
0.045
N
N
O
N
7
8
9
iso-Butyl
tert-Butyl
0.37+0.16
7.6
0.032 0.026
1.88
N
O
2
H
10
11
12
13
14
15
2,2,2-Trifluoroethyl
Methoxy ethyl
2-Diethylaminoethyl
1-Phenethyl
Cyclohexyl
3-((Tetrahydrofuran-2-
yl)methyl)
4.54 1.19
1.22 0.54
4.88
0.94 0.32
0.71 0.31
0.52 0.13
0.763
0.124
0.303
0.297
0.088
0.068
Figure 2. Conformational constraint provided potent thiazolidinone 2.
(MK-0974), a CGRP receptor antagonist with improved oral bio-
availability but limited CNS exposure (Fig. 1).
Examining the structure of olcegepant, we hypothesized that
reduction of its peptidic nature and lowering the molecular weight
and PSA could improve oral bioavailability and provide an antago-
nist with better physicochemical properties. Our initial approach
involved screening of smaller fragments of olcegepant to assess
their CGRP receptor binding. This effort led to the identification
of 1 (Table 1) which showed modest competitive binding in a
16
17
18
19
20
neo-Pentyl
Phenyl
4-Fluorobenzyl
Methyl-3-pyridyl
Ethyl-2-pyridyl
0.25 0.18
2.94
0.75 0.1
0.80 0.39
1.37
0.009 0.006
0.806
0.056
0.26
0.202
a
IC50 b-lactamse assay (n P 3) with cells treated with CGRP, compound and
cAMP antibody and represents cellular inhibition of cAMP production.
Ki Binding assay (n P 3) SK-N-MC membrane treated with 125I-CGRP, com-
b
[
125I]CGRP receptor radioligand binding assay and had significantly
pound and Ki = IC50/(1+[radioligand]/Kd) was calculated.
reduced molecular weight (MW 664).6 Compound 1 was further
tested for its functional ability to inhibit CGRP-stimulated cellular
cAMP production using a reporter assay7 and was found to be mod-
erately potent.
bond coupling conditions (HATU and DIEA in DMF at ambient
temperature).
We subsequently hypothesized that applying a degree of con-
formational constraint to 1 could potentially improve the potency
of this molecule. Several cyclic cores incorporating these features
were tested (data not shown) and thiazolidinone 2, which showed
a three-fold gain in CGRP receptor binding compared to 1, was se-
lected for further SAR exploration (Fig. 2).
The thiazolidinone scaffold was especially well suited for paral-
lel synthesis using mercaptosuccinic acid (MSA) and a large pool of
aldehydes and amines as reagents. This three-component synthesis
involved formation of the imine and treatment of the reaction mix-
ture with MSA in one pot to give the racemic thiazolidinone acetic
acid.8 Thus compound 2 was prepared (Scheme 1) from the reac-
tion of MSA and the imine generated from benzaldehyde and iso-
pentyl amine, and subsequent coupling of the resulting
thiazolidinone acetic acid with dihydroquinazolinone using amide
The encouraging data for compound 2 prompted our initial SAR
exploration of the thiazolidinone ring focusing on the amide nitro-
gen and phenyl ring substituents, in an effort to improve CGRP
receptor binding and functional cAMP activity. Several thiazolidi-
nones with N-alkyl and aromatic moieties were prepared. SAR of
this series showed that aliphatic hydrophobic groups on the thia-
zolidinone core improved CGRP binding. Long chain and branched
alkyl groups such as 8 improved binding while N-aryl substituted
thiazolidinones such as 17 showed a loss in CGRP receptor binding
compared to 2. Compound 16, with a neo-pentyl side-chain
showed a seven-fold gain in binding along-with a two-fold gain
in functional cAMP inhibition. We speculate that this side-chain
of 16 may be accessing the same hydrophobic pocket where the
side-chain of the lysine residue of olcegepant resides in the CGRP
O
SH
S
CHO
+
+
OH
a
N
HO
NH2
HO
O
86 %
O
O
b
O
S
80 %
N
N
O
N
N
H
O
2
Scheme 1. Synthesis of thiazolidinones from MSA, benzaldehyde and isopentylamine. (a) DMF, 80 °C; (b) 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one, HATU, DIEA,
DMF, RT.

P. Joshi et al. / Bioorg. Med. Chem. Lett. 24 (2014) 845–849
847
Table 4
Effect of stereochemistry on thiazolidinone ring
N
N
2
N
S
5
O
N
O
N
N
H
O
a
Compound
Diastereomer
IC50
(l
M)
Kib
(lM)
35
36
37
38
(2R, 5S)
(2R, 5R)
(2S, 5R)
(2S, 5S)
0.004 0.002
0.098 0.114
0.01 0.006
13.9 12.5
0.002 0.001
0.01 0.011
0.0009 0.0005
1.8
0
a
IC50 b-lactamse assay (n P 3) with cells treated with CGRP, compound and
cAMP antibody and represents cellular inhibition of cAMP production.
Figure 3. Structure of olcegepant in the N-terminal ectodomain of CLR-RAMP1
b
Ki Binding assay (n P 3) SK-N-MC membrane treated with 125I-CGRP, com-
complex.9
pound and Ki = IC50/(1+[radioligand]/Kd) was calculated.
receptor. Polar side chains as exemplified by methoxy methyl ether
11 and diethylamino thiazolidinone 12 showed three to five-fold
loss in CGRP receptor binding (Table 2).
Table 5
Effect of replacement of quinazolinone (n = 1) with benzodiazepinone (n = 2)
The structure of olcegepant with the N-terminal ectodomain
complex of CGRP receptor is published.9 The drug binds in an ex-
tended conformation stretching ꢀ18 Å from a hydrogen bond do-
nor-site at Thr122 of CLR, across the interface with RAMP-1 and
N
N
S
N
N
deep into a hydrophobic pocket formed by helix
lix R2 of RAMP1. RAMP1 residues Trp74 (helix
the loop connecting RAMP1 helices R2 and R3) form the ceiling
a
C1 of CLR and he-
O
O
n
a
aR2) and Trp84 (in
N
a
a
N
H
O
and back surface of the hydrophobic pocket. The quinazolone moi-
ety of olcegepant forms a hydrogen bond donor–acceptor pair with
the backbone NH and carbonyl Thr 122. The lysine amino group of
olcegepant forms a salt-bridge with the RAMP1 Asp71 side chain
carboxyl, while the indole of RAMP1 Trp74 stacks with the ali-
phatic portion. Finally, the terminal pyridyl stacks with the CRLR
Phe92 and also makes a hydrogen bond with the side chain car-
boxyl of CRLR Asp94 (Fig. 3).
a
Compound
IC50
(lM)
Kib
(lM)
27
39
n = 1
n = 2
0.042 0.02
0.019 0.013
0.002 0.002
0.002 0.0002
a
IC50 b-lactamse assay (n P 3) with cells treated with CGRP, compound and
cAMP antibody and represents cellular inhibition of cAMP production.
Ki Binding assay (n P 3) SK-N-MC membrane treated with 125I-CGRP, com-
b
pound and Ki = IC50/(1+[radioligand]/Kd) was calculated.
Table 3
Effect of substitution (R2) on the phenyl group of thiazolidinone ring
R2
O
S
N
N
O
N
N
H
O
R2
IC50
(l
M)
Kib
(lM)
a
Compound
21
22
23
24
25
26
27
28
29
30
31
32
33
34
2-Fluoro
2,3-Difluoro
2,4-Difluoro
2,6-Difluoro
2-Piperazine
2-Morpholine
2-N-Methylpiperazine
2-(4-Hydroxypiperidine)
2-(1H-Imidazol-1-yl)
2-(1H-Pyrazol-1-yl)
2-(2-(Pyridin-3-yl)
2-(2-(Pyridin-4-yl)
2-(2-(4-Butylpiperazin-1-yl)
0.18 0.05
0.21 0.07
0.19 0.09
0.17 0.11
0.06 0.02
0.16
0.04 0.02
0.044 0.005
0.086 0.034
0.062 0.018
0.088 0.06
0.099 0.001
0.044 0.005
0.036 0.004
0.054
0.118
0.03
0.059
0.002 0.001
0.052 0.022
0.002 0.002
0.018 0.006
0.007 0.0009
0.04 0.008
0.022 0.013
0.02
0.003 0.002
0.008 0.011
2-(4-(2-Hydroxyethyl)piperazin-1-yl)
a
IC50 b-lactamse assay (n P 3) with cells treated with CGRP, compound and cAMP antibody and represents cellular inhibition of cAMP production.
Ki Binding assay (n P 3) SK-N-MC membrane treated with 125I-CGRP, compound and Ki = IC50/(1+[radioligand]/Kd) was calculated.
b

848
P. Joshi et al. / Bioorg. Med. Chem. Lett. 24 (2014) 845–849
Table 6
CGRP receptor. All four diastereomers (35–38) were separated by
Effect of substitutions R2 and R3 on thiazolidinone ring
chiral SFC and tested in both the binding and cAMP inhibition as-
says (Table 4). The (2R, 5S) diastereomer 35 was found to be the
most potent isomer in both the assays. The relative stereochemical
assignment of 35 was based on NOE experiments which showed a
strong NOE from the proton at the C-2 position to the proton at the
C-5 position, thus proving their cis-relationship.
During the course of this study, we observed that the com-
pounds bearing the dihydroquinazolinone moiety underwent ben-
zylic oxidation over time at ambient temperatures to give the
quinazolinone, as previously reported.4 Therefore, we replaced
the six-membered dihydroquinazolinone core with the seven
membered benzodiazepinone system as exemplified by compound
39. Compound 39 retained CGRP receptor binding and functional
activity compared to dihydroquinazolinone 27. (Table 5). The ben-
zodiazepinone series did not suffer from oxidative degradation and
was used for subsequent SAR explorations.
Probing alkyl substitution of the piperazine nitrogen atom
showed that the tert-butyl group was preferred as increased lipo-
philicity on the piperazine increased binding to the CGRP receptor
(R1 = tBu > iPr > Et > Me).
Although the initial fluoro-substitution of the aromatic ring of
thiazolidinones (21) showed only a modest gain in receptor bind-
ing, combining the fluoro- substituent with the 20-tert-butyl piper-
azine group showed marked improvement in CGRP receptor
binding and cAMP inhibition. This effort led to thiazolidinone 48
(Table 6).
R3
N
R2
N
O
N
S
N
N
H
N
O
O
a
Compounds
R2
R3
IC50
,
(
lM)
Kib
(lM)
40
41
42
43
44
45
46
47
48
H
H
H
0.033 0.005
0.019 0.013
0.003 0.002
0.084 0.005
0.072 0.023
0.065 0.021
0.002 0.0002
0.001 0.00001
0.002 0.0002
0.0005 0.0005
0.014 0.018
0.014 0.018
0.001 0.001
0.00007 0.00001
0.00002 0.00002
0.0001 0.00007
Me
Me
Me
Me
Me
Et
30-Fluoro
40-Fluoro
50-Fluoro
60-Fluoro
30-Fluoro
30-Fluoro
30-Fluoro
iPr
tBu
0.0003 0.0001
0.0006 0.0003
a
IC50 b-lactamse assay (n P 3) with cells treated with CGRP, compound and
cAMP antibody and represents cellular inhibition of cAMP production.
b
Ki Binding assay (n P 3) SK-N-MC membrane treated with 125I-CGRP,
compound and Ki = IC50/(1+[radioligand]/Kd) was calculated.
Table 7
Effect of stereochemistry on thiazolidinone ring for 48
Based on our earlier observations that the (2S, 5S) diastereomer
was the most potent thiazolidinone core, we needed to prepare the
enantiomerically pure (S)-MSA isomer. Thus MSA was resolved
using a literature procedure to yield enantiomerically pure (S)-
enantiomer.11 (S)-MSA was subjected to the thiazolidinone reac-
tion (Scheme 1) to give a mixture of diastereomeric acids. This acid
mixture was coupled with benzodiazepinone and the resulting
products were separated using reverse phase preparative chroma-
tography using acetonitrile and water mixtures to give the desired
products.
The pure (2R, 5S) and (2S, 5S) diastereomers 49 and 50 were
tested in both the binding and cAMP inhibition assays. It was ob-
served that the (2R, 5S) enantiomer 49 was the more potent isomer
in both the binding and cAMP assay (Table 7). This was consistent
with our earlier studies which showed that the preferred configu-
ration at C-5 position was (S).
N
F
N
2
O
N
S
N
N
H
N
5
O
O
a
Compound
IC50
(lM)
Kib
(lM)
49
50
0.001 0.0009
0.046 0.01
0.00003 0.00003
0.001 0.001
a
IC50 b-lactamse assay (n P 3) with cells treated with CGRP, compound and
cAMP antibody and represents cellular inhibition of cAMP production.
Ki Binding assay (n P 3) SK-N-MC membrane treated with 125I-CGRP, com-
b
pound and Ki = IC50/(1+[radioligand]/Kd) was calculated.
With the structural information, we next focused on the effect
of phenyl ring substitution (R2) of the thiazolidinone (Table 3) by
incorporating amine groups on the phenyl ring to mimic the lysine
amino group of olcegepant. Several amines at the 20 position were
tested and were found to have similar binding affinity but im-
proved cAMP inhibitory activity compared to 16. Thus 2-(4-meth-
ylpiperazin-1-yl)phenyl substitution of the thiazolidinone (27) and
the tert-butyl analog 33 (Table 3) retained potent CGRP receptor
binding and showed a five-fold improvement in the cAMP assay
compared to 16.
Compound 27, 47, 49, olcegepant and telcagepant were evalu-
ated in rat PK studies (Table 8), telcagepant had low iv clearance,
whereas olcegepant, 49 and 47 had similar intravenous clearance
values (approximately equal to hepatic blood flow) and 27 had
higher clearance. Telcagepant, 49, 47 and 29 had better oral expo-
sure and bioavailability (45, 13, 32, and 53%, respectively) than
olcegepant (bioavailability of <1% observed). In addition, the brain
to plasma ratio for 47 and 49 (1.51 and 0.53, respectively) are sig-
nificantly higher than that of the clinically efficacious olcegepant
(<0.03) or telcagepant (0.03). The better brain/plasma ratios for
thiazolidonones 47 and 49 can be attributed to the significant
Compound 27 (Table 3) was chosen to assess the stereochemi-
cal preference of thiazolidinone diastereomers for binding to the
Table 8
Rat PK data for select compounds
Compound
%F
AUC (mg.hr/mL)
Cmax (mg/mL)
Cl (mL/min/kg)
Brain/Plasma ratio
PSA
Olcegepant
Telcagepant
49
47
27
<1
45
13
32
53
0.26
3.32
0.53
0.65
1.6
0.87
0.55
0.41
0.12
0.26
65
27
47
65
127
<0.03
0.03
0.53
1.51
ND
176.5
97.4
79.4
79.4
79.4
Mean of n = 3; Telcagepant: 10 mg/kg in 40% PEG400/10% TPGS (
a-tocopherol vitamin E succinate)/water; 49 and 47: 10 mg/kg po in suspension vehicle; 27: 30 mg/kg in 10%
TPGS in suspension; brain to plasma ratios determined following an iv bolus at 0.25 or 1 h post-dose.

P. Joshi et al. / Bioorg. Med. Chem. Lett. 24 (2014) 845–849
849
6. Binding assay: SK-N-MC non-recombinant membrane solution was diluted
reduction in PSA (79.4) (Table 8) compared to telcagepant (PSA
97.4) and olcegepant (PSA 176.5).12 Although several features
influence brain penetration, we believe that lower molecular
weight and PSA led to improved permeability for thiazolidinone
series. This led us to speculate that the thiazolidinone series of-
fered potential for development of potent, CNS-penetrant CGRP
receptor antagonists for the treatment of migraine.
In summary the thiazolidinone series afforded very potent
CGRP receptor antagonist with lower molecular weights (693 and
707 for compounds 47 and 49, respectively) vs. 855 for olcegepant.
In rat PK/tissue distribution studies, increased brain exposure for
47 and 49 compared to olcegepant and telcagepant and improved
oral bioavailability for 47, 49 and 27 compared to Olcegepant was
observed.
1:40 in CGRP binding solution and homogenized for about 1 min. Then 40
this solution was plated onto 96-well round bottom plate containing 20
[5ꢁ] test compound and incubated for 30 min at room temperature. 40
lL of
l
l
L of
L of
0.125 nM 125I-CGRP solution was added to each well (final concentration of
50 pM) and incubated for 2 h at room temperature. The binding reaction was
stopped by rapid filtration over 0.5% PEI-treated GF/C filter and washed four
times with cold buffer solution. The plate was dried at 65 °C for 1 h. Each well
was treated with 50 lL of Microsinct-PS and sealed with TopSeal-A. The plate
was read on a Packard Instruments Topcount. Ki was calculated using Cheng–
Prusoff equation10 (Ki = IC50/(1 + [radioligand]/Kd), where Kd = 55 pM and IC50
are experimentally determined values.
7. b-Lactamase assay: SK-N-MC cell line endogenously expressing CGRP was
transduced with a retroviral vector containing a transcription reporter, b-
lactamase gene downstream of cAMP responsive promoter. b-Lactamase
activity was measured using a fluorescence energy transfer (FRET) dye, CCF4/
AM (Zlokarnik, G.; Negulescu, P. A.; Knapp, T. E.; Mere, L.; Burres, N.; Feng, L.;
Whitney, M.; Roemer, K.; Tsien, R. Y. Science 1998, 279, 84). 30,000 cells/well
were plated in growth medium (MEM+10% FBS) in poly-D-lysine coated black
well and clear bottom, 384 well plate (Greiner) and allowed to grow overnight
in regular growth conditions (37 °C, 5% CO2). The following day, growth
Acknowledgment
medium was removed and replaced with 30
FBS) + compound and pre-incubated for 30 min. After pre-incubation, 10
well of [4ꢁ] 0.8-nM of CGRP peptide was added (final concentration of
200 pM). The plate was incubated for 3 h (37 °C, 5% CO2) and 10 ° L of CCF4/
l
L/well of assay media (MEM+1%
lL/
We thank Dr. Michael DeNinno and Michael Badia for critical
review of the manuscript.
l
AM was added across plate. The plate was incubated for additional 2 hrs at
room temperature and read at tcPR, a Vertex proprietary fluorescence plate
reader.
References and notes
8. Representative experimental procedure: To
a
mixture of benzaldehyde
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Vacca, J. P.; Williams, T. M. Bioorg. Med. Chem. Lett. 2007, 17, 4795.
(20.1 mg, 0.2 mmol) and isopentyl amine (16 mg, 0.2 mmol) in 500
lL
DMF was added mercaptosuccinic acid (45 mg, 0.3 mmol) and the mixture was
heated at 80 °C for 16 h. The reaction mixture was cooled and partitioned
between ethyl acetate and water. The organics were separated and dried and
solvent removed to give the thiazoldinone acetic acid. The acid (31 mg,
0.1 mmol) was coupled with 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-
one (23 mg, 0.1 mmol) using HATU (38 mg, 0.1 mmol) in the presence of
diisopropyl ethyl amine (44 lL, 0.25 mmol) in 300 lL of DMF at ambient
temperature, and was purified with 10–90% acetonitrile/water to give 3-
isopentyl-5-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidin-1-
yl)ethyl)-2-phenylthiazolidin-4-one as the desired product.
9. ter Haar, E.; Koth, C. M.; Abdul-Manan, N.; Swenson, L.; Coll, J.; Lippke, J. A.;
Garcia-Guzman, M.; Moore, J. M. Structure 2010, 18(9), 1083–1093.
10. Cheng, Y.; Prusoff, W. H. Biochem. Pharmacol. 1973, 22, 3099.
11. Shiraiwa, T.; Ohkubo, M.; Kubo, M.; Miyazaki, H.; Takehata, M.; Izawa, H.;
Nakagawa, K.; Kurokawa, H. Chem. Pharm. Bull. 1998, 46, 1364.
12. Hitchcock, S. A.; Pennington, L. D. J. Med. Chem. 2006, 49(26), 7559.