Substituted azaquinazolinones as modulators of GHSr-1a for the treatment of type II diabetes and obesity

Article abstract of DOI:10.1016/j.bmcl.2012.01.078

Substituted azaquinazolinones were identified as antagonists of the GHSr-1A receptor for the treatment of type II diabetes and obesity. Optimisation for potency and Log D lead to the identification of orally bioavailable, potent antagonists with improved selectivity over hERG.

Full text of DOI:10.1016/j.bmcl.2012.01.078

Bioorganic & Medicinal Chemistry Letters 22 (2012) 2271–2278
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Substituted azaquinazolinones as modulators of GHSr-1a for the treatment
of type II diabetes and obesity
Patrick Hanrahan a, , James Bell c, Gillian Bottomley b, Stuart Bradley a, Phillip Clarke a, Eleanor Curtis c,
⇑
Susan Davis a, Graham Dawson a, James Horswill b, John Keily a, Gary Moore b, Chrystelle Rasamison a,
Jason Bloxham a
a Medicinal Chemistry, Prosidion Ltd, Windrush Court, Watlington Rd, Cowley, Oxford OX4 6LT, United Kingdom
b In vitro Pharmacology, Prosidion Ltd, Windrush Court, Watlington Rd, Cowley, Oxford OX4 6LT, United Kingdom
c Research Technologies, Prosidion Ltd, Windrush Court, Watlington Rd, Cowley, Oxford OX4 6LT, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
Substituted azaquinazolinones were identified as antagonists of the GHSr-1A receptor for the treatment
of type II diabetes and obesity. Optimisation for potency and LogD lead to the identification of orally bio-
available, potent antagonists with improved selectivity over hERG.
Received 13 December 2011
Revised 20 January 2012
Accepted 21 January 2012
Available online 1 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Diabetes
Obesity
Azaquinazolinone
Ghrelin
Prosidion
LipE
According to the American Diabetes Association,1 the direct
costs in 2007, of treating the estimated 23.6 million type 2 diabetes
mellitus (T2DM) patients and the estimated 57 million pre-dia-
betic patients2 in the United States was approximately $116 billion
with an additional $58 billion dollars in indirect costs. Wild et al.3
have predicted that the number of patients worldwide, suffering
from T2DM will rise to over 360 million by 2030. Many of the cur-
rent therapies for T2DM suffer from the fact that they are prone to
causing an increase in body weight.4 Ghrelin has previously been
shown to affect both appetite and body weight. Short term fasting
has been demonstrated to cause an increase in systemic ghrelin
levels, whereas infusion of ghrelin has been shown to stimulate
appetite and promote spontaneous food in-take. Ghrelin has also
been shown to have long term effects upon body weight. Ghrelin
not only stimulates feeding but it also shown to affect energy
homeostasis.5 It has also been demonstrated that ghrelin impedes
the ability of insulin to suppress endogenous glucose production.
Acute administration of ghrelin to humans causes an increase in
plasma glucose levels. This effect may not solely result from direct
effects on hepatocytes; where ghrelin has been shown to modulate
glycogen synthesis and gluconeogenesis; but also by stimulation of
hepatic glucose production.6 The reduction of food intake, with
subsequent weight loss and the growing body of evidence suggest-
ing increased insulin secretion and improved glucose tolerance
in vivo make small molecule antagonists of the Growth hormone
secretagogue receptor (GHS-R1a) receptor of great interest as
drugs for the treatment of diabetes coupled with meaningful body-
weight loss.
Several examples of structurally diverse small molecule GHS-
R1a antagonists had previously been reported in the literature
(Fig. 1).7–9
Compounds 1 and 3 were profiled further in-house to examine
for any potential liabilities in each structural class. Once this profil-
ing was complete, YIL-781 (1) was selected as a starting point for a
fast follow-on approach to run in parallel to a program using in-
house chemical matter. Compound 1 represented an attractive
point, low molecular weight (410 Da) with good LipE (6.54). Whilst
potent against GHS-R1a; in our hands compound 1 carried a signif-
icant potassium ion channel (hERG) liability (IC50 1.6
lM) and
showed >50% activity at 10 M at several targets, for example the
l
muscarinic receptors, M1 and M2, and the serotonin receptor,
5HT2b in a Cerep metabolic screen. This presented an interesting
challenge to the drug discovery team, designing molecules that
maintained (or improved) the activity at the GHS-R1a receptor,
whilst reducing the liability at hERG and other targets. Rudolph
⇑
Corresponding author.
E-mail address: hanrahanpatrick@yahoo.co.uk (P. Hanrahan).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2012.01.078

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P. Hanrahan et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2271–2278
N
N
N
N
N
N
N
O
N
N
N
N
O
N
O
N
Cl
N
Cl
N
c
N
a
b
O
N
Cl
O
O
–O
O
N+
O
(S)
N
d
O
F
7
8
9
JMV 3008
IC50 5.6nM
YIL-781
Scheme 2. Reagents and conditions: (a) SnCl2Á2H2O, EtOH, reflux, 2 h, 59%; (b)
concd HCl, 90 °C, 5 h, quant; (c) C-((R)-1-isopropylpiperidine-3-yl)methylamine,
HOBt, EDCI, NEt3, DMF, 18 h, 45 °C, 50%; (d) 1,1,1-triethoxy ethane, AcOH, reflux,
3 h, 70%.
Ki 4.0nM
1
2
N
N
N
O
N
O
N
N
O
O
N
Cl
a
b
O
Cl
N
N
N
13d
IC50 188nM
3
N
11
10
Scheme 3. Reagents and conditions: (a) C-((R)-1-isopropylpiperidine-3-yl)methyl-
amine, HOBt, EDCI, NEt3, DMF, 45%; (b) 1,1,1-triethoxy ethane, AcOH, reflux, 3 h,
94%.
Figure 1. Literature examples of small molecule GHS-R1a antagonists.
et al. had previously demonstrated that modification of the basicity
(pKa) of the piperidine nitrogen resulted in no significant reduction
in activity at GHS-R1a, but also had no significant effect on plasma
exposure levels.7 Our aim was to investigate reduction of the LogD
of the molecules in an attempt to improve selectivity levels and also
to move away from lipophilic amino compounds, often associated
with having hERG liabilities.10 This account will highlight our main
strategy; modification of the lipophilicity of the central core, mov-
ing from a quinazolinone type structure (as exemplified by 1) to the
azaquinazolinone type structures as exemplified in Figure 2: lead-
ing to the discovery of potent, selective GHS-R1a antagonists with
improved activity against hERG.
N
N
O
N
I
O
O
a
b
I
N
N
N
12
13
Scheme 4. Reagents and conditions: (a) C-((R)-1-isopropylpiperidine-3-yl)methyl-
The commercially available anthranilic acids 4, 10 and 12 were
coupled to C-((R)-1-isopropylpiperidine-3-yl)methylamine11 using
HOBt and EDCI. Compound 8 was synthesised in moderate yield
from the commercially available nitrile–nitro compound [7]. The
amine, HOBt, EDCI, NEt3, DMF, 57%; (b) 1,1,1-triethoxy ethane, AcOH, reflux, 3 h,
90%.
N
N
N
N
N
O
O
N
O
N
X
O
a
O
Ar
(S)
X = N or
Y = N or
Z = N or
+
Ar
X
Y
O
N
N
N
Ar
z
N
X and Y = N
X = Cl, Br
Figure 2. Azaquinazolinone cores.
Scheme 5. Reagents and conditions: (a) Cs2CO3, DMF, 120 °C,
lW, 30 min: 40–80%.
N
O
N
N
N
N
N
N
N
N
N
Br
a
O
b
O
O
N
O
N
O
N
N
Br
N
N
Br
N
O
I
a
Ar
O
+
Ar
N
N
N
N
5
4
6
13
Scheme 1. Reagents and conditions: (a) C-((R)-1-isopropylpiperidine-3-yl)methyl-
amine, HOBt, EDCI, NEt3, DMF, 18 h, 45 °C, 90%; (b) 1,1,1-triethoxy ethane, AcOH,
reflux, 3 h, 70%.
Scheme 6. Reagents and conditions: (a) Cs2CO3, NMP, CuCl, TMHD, 125–150 °C, 7–
35%

P. Hanrahan et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2271–2278
2273
Table 1
8-Azaquinazolinone SAR
N
O
O
Ar
N
N
N
No.
Ar
GHS-R1a Ki (nM)
GHS-R1a IC50 (nM)
LipE
6.86
ACD LogD
14
6.7
357
26
1.32
1.98
F
F
15
16
0.16
1.7
7.82
6.23
Br
131
2.53
Table 2
5-azaquinazolinone SAR
N
N
O
N
N
O
Ar
No.
Ar
GHS-R1a Ki (nM)
GHS-R1a IC50 (nM)
185
LipE
8.13
ACD LogD
17
2.0
0.57
F
F
18
0.2
2.0
9.20
0.49
Cl
O
19
20
0.9
19.2
2.7
8.86
0.18
0.11
O
S
0.01
10.75
N
F
21
22
0.01
3.1
2.3
9.87
8.00
0.33
0.50
Br
O
N
N
118
23
24
2.6
0.4
131
8.12
7.57
0.46
1.78
F
37.7
nitrile was converted to the primary amide and the nitro group
was simultaneously reduced to the primary amine using SnCl2,
followed by acid catalysed hydrolysis to the acid as in moderate
overall yield, as shown in Scheme 1. Compound 8 was coupled to

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P. Hanrahan et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2271–2278
Table 3
7-Azaquinazolinone SAR
N
O
O
Ar
N
N
N
No.
Ar
GHS-R1a Ki (nM)
GHS-R1a IC50 (nM)
LipE
7.83
ACD LogD
25
3.4
399
146
0.63
F
F
26
0.2
9.08
0.56
Cl
O
27
28
0.3
86.5
9.23
9.78
0.25
0.19
O
S
0.10
29.2
N
N
29
30
6.6
0.5
1440
7.57
9.65
0.61
F
N
137
À0.38
N
C-((R)-1-isopropylpiperidine-3-yl)methylamine using HOBt and
EDCI, giving the resulting amide intermediate in moderate yield.
The amide intermediates were heated to reflux in a 1:1 mixture
of AcOH and 1,1,1-triethoxy ethane to give the azaquinazolinone
intermediates 6, 9, 11 and 13 in excellent yields. (Scheme 1–4).
SNAr reactions of intermediates [6, 9 and 11] with selected aryl
alcohols, using Cs2CO3 in DMF under microwave conditions, gave
the desired biaryl ethers in moderate to excellent yield as outlined
in Scheme 5.
Attempts to synthesis biaryl ethers from compound 13 and
other halo analogues using the same SNAr conditions were unsuc-
cessful. Similarly conversion of the iodo compound 13 to a boronic
acid intermediate followed by Chan–Lam couplings12 also proved
to be unsuccessful (due to the difficulty in isolating the boronic
acid intermediate), whilst attempts to apply Buchwald–Hartwig13
methodology met with very limited success. Modified Ullmann
coupling conditions, using a stoichiometric amount of CuCl and
2,2,6,6-tetramethyl-3,5-heptanedione(THMD) ligand, as outlined
in Scheme 6 proved to be more successful. The yields of recovered
material however remained poor, with <35% being recorded for all
analogues synthesised.
The in vitro SAR studies were carried out as follows: Binding
affinities (Ki) for GHS-R1a were determined using an 125I-ghrelin
displacement assay (saturation binding assay, Millipore human
GHS-R1a membranes) and the functional activities (IC50) were
determined using a FLIPR Ca2+ mobilisation assay. A more detailed
description of the assays is given by Bloxham et al.11 and in the Sup-
plementary data. hERG assays were performed at Essen Biosciences
(mini-patch clamp).14 LipE, also known as ligand-lipophilicity effi-
ciency (LLE) was calculated using the formula [pKi À ACD LogD].
Compound 1 in our hands had Ki of 1.0 nM in the competition
binging assay, an IC50 of 141 nM in the FLIPR assay, a calculated
LogD of 2.34 and a LipE value of 6.54. Addition of hetero atoms into
the central core was seen as a strategy to reduce the LogD of the
molecules and maintain activity and functionality. As shown in Ta-
ble 1, whilst the binding affinity of 14 remained at a single digit
nanomolar level, it showed a twofold drop-off in functional activity
in the FLIPR assay; importantly 14 maintained full antagonist
activity at GHS-R1a. There was however no significant improve-
ment in LipE when compared to compound 1. Synthetic challenges,
as already mentioned, meant that only a limited number of 8-
azaquinazolinone were ever synthesised. Compound 15 repre-
sented the most potent compound synthesised in this series, with
sub-nanomolar binding affinity, excellent functional activity and
an improvement in LipE compared to compound 1.
It was envisaged that moving the nitrogen to the 5 position
would improve the ease of synthesis of the molecules. It was hoped
to improve ACD LogD and retain activity at GHS-R1a, thus improv-
ing LipE. Compound 17 displayed both binding affinity and func-
tional activity comparable to that of compound 1, but the
calculated LogD value was much improved, 0.57. The LipE of 17
was significantly improved as a result. Ease of synthesis lead to
greater exploration of the right side of the biaryl ether linkage,
leading to the identification of compounds (Table 2) with subn-
anomolar affinity and single digit functional activity at GHS-R1a.
The molecules also maintained antagonist activity at the receptor
and had much improved LipE compared to 1. We were able to
show that a wide variety of aryl alcohols were tolerated on the
right hand side of the molecule. Compounds 19 and 20 for exam-
ple, showed that significant improvements in binding, functional
activity and LipE could be made using 6,5 ring systems, with com-
pound 20 representing the best overall combination of binding,
activity and physicochemical properties for this series. Compounds
22 and 23 displayed comparable binding and functional activity to
compound 1 but with a much improved LipE, demonstrating that
6,6 ring systems were also well tolerated.

P. Hanrahan et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2271–2278
2275
Table 4
Pteridinone SAR
N
O
N
N
O
Ar
N
N
No.
Ar
GHS-R1a Ki (nM)
GHS-R1a IC50 (nM)
LipE
8.30
ACD LogD
31
3.1
587
102
0.20
0.13
F
F
32
0.6
9.10
Cl
O
33
34
1.5
16.5
9.00
9.83
À0.18
À0.25
O
S
0.26
5.7
N
N
F
35
36
1.9
142
8.63
8.15
0.10
1.41
F
0.27
80
37
38
0.05
5.0
1.17
9.46
9.12
0.86
Br
N
51.8
À0.82
N
Following on from the 5-azaquinazolinones, the nitrogen was
again moved around the ring to the 7 position. Compound 25, as
with compound 17, showed excellent affinity for the GHS-R1a
receptor; however it suffered a twofold drop off with respect to
functional activity when compared to compound 1. This effect
was noted across the series. Applying some the SAR knowledge de-
rived from the 5-aza series we were able to identify compounds
with subnanomolar binding affinity, as seen in Table 3. However
comparing the functional activities of the compounds to 1 or the
isomeric nitrogen match pair for example, comparing compounds
18 and 26 or compounds 23 and 29, there was at least a twofold
drop in functional activity and in some cases the drop off was
>10-fold. Whilst the LipE values of the molecules were improved
with respect to compound 1, the functional activities of the 7-aza
molecules were disappointing.
When we examined the data from the other series it was clear
that we had been successful in lowering the LogD of the molecule
and had succeeded in improving in binding and activity, thus
improving LipE compared to 1. We decided to explore whether
we could further lower the LogD of our compound by the introduc-
tion of an additional heteroatom into the central core, and could
the improvements seen in binding and functional activity seen in
the 5 and 8-aza compounds be maintained. This led to the discov-
ery of compound 31, a compound with excellent binding affinity
for the GHS-R1a receptor but which suffered a fourfold drop in
functional activity at the receptor. Applying the knowledge gained
from the 5 and 8-aza compounds, we were able to identify com-
pounds with excellent binding affinities, comparable or better
functional activities when compared to 1 (Table 4). As with the
5-aza series, a wide variety of aryl substituents were tolerated on
the right hand side of the molecule. By analogy to compound 17,
compound 34 with the benzothiazol-6-ol right hand side, gave a
molecule with the best combination of binding, functional activity
and physicochemical properties.The main driver behind reducing
the LogD of our molecules was to reduce the potential hERG liabil-
ity we identified during the initial profiling of compound 1. With
compounds 14 and 17 we were able to show moderate improve-
ment in the hERG IC50, as shown in Table 5. In the case of com-
pound 25, there was no improvement in hERG with respect to
compound 1. However with compound 31, we were able to achieve
a 10-fold improvement in hERG IC50. With compound 18, when the
lipophilicity of the right hand side of the biaryl ether was increased
we lost the improvement in hERG IC50 observed with compound 14
and in the case of compound 26, we observed a 10-fold increase in
activity at hERG. Compound 32 maintained the improvement at
hERG shown by 31, with an IC50 > 33 lM. Although the design of
our molecules was driven by improvements in bulk LogD, we ret-
rospectively believe we have observed local LogD and/or shape/
configuration components to the hERG SAR. Researchers at Ver-
tex10 previously reported observing a connection between shape/
conformation and the potential for hERG channel blockade. As ex-
pected, there is a clear trend towards increased activity at hERG

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P. Hanrahan et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2271–2278
Table 5
hERG SAR
N
O
O
Ar
N
N
N
No.
Core
Ar
GHS-R1a IC50 (nM)
141
hERG IC50
1.6
(l
M)
hERG pIC50
5.79
ACD LogD
O
1
2.34
F
F
F
F
N
O
17
25
185
399
3.2
1.3
5.49
5.89
0.57
0.63
O
O
N
14
31
357
587
3.1
5.51
4.79
1.32
0.20
N
N
O
O
16.1
F
N
N
F
F
F
18
32
26
2.0
1.3
5.89
4.48
6.89
0.49
0.13
0.56
Cl
Cl
Cl
N
N
O
O
O
102
>33
N
N
146
0.13
N
29
22
35
1440
118
9.4
13.6
>33
5.02
4.87
4.48
0.61
0.50
0.10
F
N
O
O
O
N
N
N
N
142
F
S
O
O
28
39
29.2
2.4
5.62
4.60
0.19
0.11
N
N
N
N
2180
25.1
with increasing LogD. However, several outliers are quite apparent
from the plots shown in Graph 1 and Graph 2.
In the case of the 7-aza molecules, activity at hERG was in
general at best similar to that of 1. Compound 25, the isomeric
nitrogen match pair of 1, whilst having a 2-Log unit difference in
0.13 lM. When we moved to quinolin-8-ol derived right hand
sides similar to those as exemplified by 29 we saw a marked,
and unexpected, improvement in hERG activity, beyond what we
believe to be the contribution from lowering LogD alone. Com-
pound 28 whilst having a calculated LogD of 0.19, has a hERG
the calculated LogD, had an IC50 of 1.3
l
M. Compound 26 has a
IC50 of 2.4
lM, a moderate improvement, but not statistically sig-
similar calculated LogD value however the hERG IC50 was
nificant within the parameters of the assay. We hypothesised that

P. Hanrahan et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2271–2278
2277
Graph 1. LogD versus pIC50
.
Graph 2. LogD versus pIC50
.
having the nitrogen in 7-position, allows the molecule to adopt a
conformation favourable to blocking the hERG channel. With the
larger, spatially demanding substituted quinolin-8-ol derivatives,
we believe the conformation adopted is no longer favourable.

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P. Hanrahan et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2271–2278
Table 6
Acknowledgments
Pharmacokinetic profile of compounds 17, 18 and 31
Compound
18
Many thanks to Dr. Craig Johnstone, head of Medicinal Chemis-
try, for the tremendous amount of advice, discussion and time gi-
ven during writing. A big thank you to Dr. Linda Hirons, Research
Technologies, for her help in analysing the hERG data and finally
thank you to Dr. Andreas Scheel, head of in vitro pharmacology
for help and discussion with the assay protocols.
17
31
Route
iv
po
3.0
iv
po
iv
1.0
1172a
1.87
3.01
13
po
3.0
1171a
0.52
Dose (mg/kg)
1.0
1.0
3.0
AUC (mg h/L)
Cmax (ng h/ml)
T1/2 (h)
Cl (ml min/kg)
Vss (L/kg)
523
0.47
7.16
32
11.95
60
941
0.18
695
0.89
4.71
24
736
0.16
Supplementary data
6.64
35
2.87
F (%)
33a
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2012.01.078.
a
See note in text.
References and notes
Similarly with the 5-aza compounds, in general the hERG IC50’s re-
corded were around 3–4 M, or twofold better when compared to
l
1. Dall, T.; Edge Mann, S.; Zhang, Y.; Martin, J.; Chen, Y.; Hogan, P. Diabetes Care
2008, 31, 596.
2. Centers for Disease Control and Prevention. National diabetes fact sheet:
general information and National Estimates on Diabetes in the United States,
2007; U.S. Department of Health and Human Services, Centers for Disease
Control and Prevention: Atlanta, GA, 2008.
3. Wild, S.; Roglic, G.; Green, A.; Sicree, R.; King, H. Diabetes Care 2004, 27, 1047.
4. Bailey, C. J. Curr. Diab. Rep. 2005, 5, 353.
5. Zhao, H.; Liu, G. Curr. Opin. Drug Discov. Devel. 2006, 9, 509. and references
therein.
1. Compound 22 however showed a marked improvement in hERG
activity, 10-fold when compared to 1. Due to the limited number of
compounds synthesised in the 8-aza series we are unable to dis-
cern any useful information with any degree of certainty. The re-
sults from the Pteridinone series of compounds seem to be
driven largely by LogD.
PK experiments were performed in male SD rats, using 20%
trappsol_WFI as the vehicle. Compounds 17, 18 and 31 were taken
forward as representative examples for pharmacokinetic profiling.
As a consequence of reducing lipophilicity, compounds can often
become less bioavailable due to lower permeability. Compounds
17 and 31 were chosen as direct comparators for compound 1.
Compound 18 was selected for PK profiling to determine suitability
to progress to OGTT. As can be seen from Table 6, all of the com-
pounds were orally absorbed. We were unable to calculate a per-
centage bioavailability for 31 using the standard calculation due
to difficulties extrapolating the concentration versus time plot to
infinity with a high degree of confidence; the bioavailability was
6. Dezaki, K.; Hosoda, H.; Kakei, M.; Hashiguchi, S.; Watanabe, M.; Kangawa, K.;
Yada, T. Diabetes 2004, 53, 3142.
7. Rudolph, J.; Esler, W. P.; O’Connor, S.; Coish, P. D. G.; Wickens, P. L.; Brands, M.;
Bierer, D. E.; Bloomquist, B. T.; Bondar, G.; Chen, L.; Chuang, C.-Y.; Claus, T. H.;
Fathi, Z.; Fu, W.; Khire, U. R.; Kristie, J. A.; Liu, X.-G.; Lowe, D. B.; McClure, A. C.;
Michels, M.; Ortiz, A. A.; Ramsden, P. M.; Schoenleber, R. W.; Shelekhin, T. E.;
Vakalopoulos, A.; Tang, W.; Wang, L.; Yi, L.; Gardell, S. J.; Livingston, J. N.;
Sweet, L. J.; Bullock, W. H. J. Med. Chem. 2007, 50, 5202.
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estimated using AUC0–last
.
In summary using 1 as a starting point, using LipE as a key mea-
sure of improvement, we have identified a number of orally bio-
available, potent, selective GHS-R1a antagonists, with an
improved profile against the hERG potassium channel. We have
been able to demonstrate that lowering of LogD has resulted in
an initial drop in functional activity against GHS-R1a but that by
careful selection of aryl substituents we have been able to recover
this activity and maintain improved profiles against hERG.
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