The discovery and optimisation of benzazepine sulfonamide and sulfones as potent agonists of the motilin receptor

Article abstract of DOI:10.1016/j.bmcl.2009.09.027

Optimisation of a series of benzazepine sulfonamide hit compounds identified from high throughput screening led to the discovery of a new series of tractable, potent motilin receptor agonists.

Full text of DOI:10.1016/j.bmcl.2009.09.027

Bioorganic & Medicinal Chemistry Letters 19 (2009) 6452–6458
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The discovery and optimisation of benzazepine sulfonamide and sulfones
as potent agonists of the motilin receptor
c,
d
a
b
c
James M. Bailey a, , Jackie S. Scott , Jonathan B. Basilla , Victoria J. Bolton , Izzy Boyfield , David G. Evans ,
Etienne Fleury c, Tom D. Heightman c, Emma M. Jarvie b, Kirk Lawless c, Kim L. Matthews b, Fiona McKay c,
Hindy Mok c, Alison Muir c, Barry S. Orlek b, Gareth J. Sanger a, Geoffrey Stemp a, Alexander J. Stevens a,
Mervyn Thompson b, John Ward b, Kalindi Vaidya d, Susan M. Westaway a
*
*
a Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK
b Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
c Molecular Discovery Research, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
d Molecular Discovery Research, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Optimisation of a series of benzazepine sulfonamide hit compounds identified from high throughput
screening led to the discovery of a new series of tractable, potent motilin receptor agonists.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 10 August 2009
Revised 4 September 2009
Accepted 5 September 2009
Available online 12 September 2009
Keywords:
Motilin
7TM
Benzazepine
Agonist
Motilin is a 22 amino acid peptide which on interaction with
the motilin G protein-coupled receptor (GPCR) is involved in regu-
lating the motor activity of the digestive system.1,2 Specifically,
activation of the motilin receptor increases contractile activity of
the gastrointestinal smooth muscle3 and promotes gastric empty-
ing.4,5 Motilin plays a key role in regulating the migrating motor
complexes (phase III), which are a series of peristaltic contractions
emanating from the stomach to the small intestine which serve to
clear this tract of residual content in the interdigestive state.2,6 Mo-
tilin is produced by endocrine cells in the upper small intestinal
mucosa and is related to another gastrointestinal hormone, ghre-
lin.1,7,8 The human motilin receptor was cloned and characterised
in 1997 and has a 52% overall amino acid sequence identity to
the ghrelin receptor.9,10
Several gastrointestinal disorders involve delayed gastric emp-
tying, for example in diabetic gastroparesis patients and some sub-
sets of functional dyspepsia patients. In these cases administration
of a gastroprokinetic agent such as a motilin receptor agonist could
alleviate symptoms. However the pathophysiology underlying
these conditions is complex, being affected by multiple factors.11
The macrolide antibiotic erythromycin is well established as a
motilin receptor agonist which increases gastric emptying,12,13
and is frequently used in the clinic for the treatment of gastric sta-
sis. However, in addition to its antibiotic activity, erythromycin
also possesses other undesirable properties such as acid instability,
increased cardiac risk factors and potential for drug–drug interac-
tions.14 Various macrolide erythromycin derivatives, or motilides,
have been developed which maintain the motilin receptor agonist
activity whilst eradicating antibiotic activity. Clinical trials in gas-
troparesis and functional dyspepsia patients with some of the early
motilides have yielded mixed results.15,16 However, more recently,
the motilide mitemcinal17 (1, Fig. 1) has shown promise in clinical
trials by improving the rate of gastric emptying18 and alleviating
symptoms in gastroparesis patients.19
As part of our ongoing program,20 we sought to identify low
molecular weight motilin receptor agonists for use in conditions
where reduced gastric emptying is a factor. There are limited
examples of non-macrolide motilin receptor agonists, for example,
221 and GSK962040 3 from our laboratories.20c In this Letter, we
disclose the discovery and optimisation of a novel series of low
molecular weight benzazepine sulfonamide and sulfone motilin
receptor agonists.
A high throughput screen (HTS) against the motilin receptor
conducted in FLIPR format22 on the GSK compound collection pro-
duced several potential series of interest. Prioritisation of these
* Corresponding author. Tel.: +44 1438 762291.
E-mail address: james.m.bailey@gsk.com (J.M. Bailey).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.09.027

J. M. Bailey et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6452–6458
6453
Me
iPr
N
O
Me
O
H
HO
N
Me
O
Me
Me
O
O
Me
O
O
N
H
CONH2
N
Me
Me
O
NH
O
Me
O
Me
O
N
N
N
Me
O
Me
OH
N
O
N
H
F
O
Me
OMe
N
H
Mitemcinal 1
2
GSK962040 3
Figure 1. Various known motilin receptor agonists.
O O
S
O O
S
N
N R
N
NH
N
N
H
H
Figure 2. Benzazepine template 4.
Potency:
h-motilin R: pEC50 8.6 (0.7)
Developability:
MW 439, clogP 4.9
Efficacy:
series, for example by profiling compounds in our rabbit isolated
gastric antrum native tissue assay,23 identified a number of com-
pounds based on the benzazepine sulfonamide template (Fig. 2)
as a suitable starting point for our chemistry programme.
Aq. Sol. 10 mg/mL (pH 7.4)
CLi (mL/min/g): rat 33, hum 22
Rabbit native tissue bath:
Emax 47% at 1µM
P450 enzyme inhibition (IC50 µM):
1A2 29, 2C9 0.6, 2C19 8.8,
2D6 <0.1, 3A4DEF 0.8, 3A4PPR 1.9
Selectivity:
h-ghrelin R pEC50 7.1 (0.7),
5HT6 fpKi 7.7,
D2/D3 pKi 7.0 / 8.4
hERG pIC50 5.6
We first investigated the effect of substitution on the benzaze-
pine nitrogen, complemented by analogue searching of the GSK
compound collection following the HTS (Table 1). The unsubstitut-
ed benzazepine 5 was only very weakly active, bulky alkyl groups
showed a small increase in potency, with cyclopentyl 6 the most
active. More polar saturated groups such as THF 7 and piperidines
8 or 9 were generally not well tolerated. A range of benzyl substit-
uents were investigated, and were weakly active or inactive, for
example the parent benzyl compound 10. Interestingly, the most
potent compound from this set was phenylacetamide 11 possess-
ing hydrogen bond donor capabilities. A similar pattern was ob-
served for thiophenes 12 and 13, where the appropriately
positioned acetamide endowed good potency and efficacy com-
pared with the unsubstituted parent. To explore this effect further,
a series of H-bond donor capable heterocycles were prepared.
Thus, imidazoles 14 and 15 displayed excellent potency and effi-
cacy whereas imidazole 16, in which the methyl group sterically
hinders the hydrogen bond donor sites, showed a marked decrease
in potency. N-Me compound 17 had no hydrogen bond donor capa-
bility and therefore displayed low potency. This SAR strongly sug-
gests that good hydrogen bond donor capability affords good
motilin receptor agonist activity in this series. The more potent
imidazoles 14–16 all showed activity at the ghrelin receptor, albeit
as partial agonists, but switching to pyrazole 18 was encouraging
with this being one of our most potent compounds to date, and
it also showed >30-fold selectivity towards the ghrelin receptor.24
Compound 18 was a good starting point in terms of potency;
but a lack of GPCR selectivity, a poor DMPK profile,25 and only
weak efficacy in our native tissue assay (Fig. 3) meant it required
further optimisation. To this end, we next focused on variation of
the lipophilic phenyl group (Table 2), in the hope that modification
would engender selectivity against other GPCR receptors and im-
prove efficacy in the rabbit native tissue assay. Reduction of log P
by introduction of more polar groups here was also expected to im-
prove the DMPK profile.
Figure 3. Benzazepine compound 18.
rophenyl 22 was weakly potent. The 3-chloro-4-methylphenyl
analogue 23 displayed moderate potency and efficacy, although
this compound also showed considerable affinity for the ghrelin,
5HT6 and D3 receptors.
para-Substituted phenyl sulfonamides generally displayed good
motilin receptor agonist potency and efficacy, with bulkier substit-
uents performing best. The 4-40-biphenyl compound 24, 4-isopro-
poxyphenyl 25 and chroman 26 all displayed high potency and
efficacy although potency against the D3 receptor was a concern,
as was rising ghrelin activity for the two ethers. All three com-
pounds also had high c log P values, leading to the hypothesis that
lipophilicity in the tail was required for motilin activity. Benzox-
azine 27 fueled our concerns, as the more polar compound was al-
most a log unit less active than ether 26. Another bicyclic
compound, pyridinylthiophene 28, exhibited high potency and
efficacy and performed well in the native tissue assay (Emax 190%
at 3 lM). Furthermore, selectivity was good but unfortunately
intrinsic clearance remained high (rat = 32, human = 15 mL/min/
g). Morpholinylpyridine 29 displayed similar potency to 28, and
had an excellent effect in the rabbit native tissue assay (Emax
476% at 1 lM). Moreover, compared to n-butylphenyl 18, both
selectivity and intrinsic clearance were greatly improved
(rat = 3.8, human = 6.6 mL/min/g). These results were very gratify-
ing, as it showed that an excellent activity profile could be ob-
tained for a compound with low c log P.
Pyridines 28 and 29 gave two of our most efficacious com-
pounds to date, 29 also showed a much improved developability
profile over 18 (Fig. 4).
Isopropyl sulfonamide 19 was inactive and benzyl sulfonamide
20 was weakly active, suggesting that more bulky substitution
here was poorly tolerated. A variety of phenyl sulfonamides were
then investigated and these displayed a range of potencies. For
example, the cyanophenyl analogue 21 was inactive whereas chlo-
However there were still issues to address with the series, in par-
ticular the CYP2D6 activity of all but two of the compounds mea-
sured in Table 2 was 61 lM, leading to a potential for drug–drug
interactions intheclinic. Wereasonedthatthepyrazolegroupwhich
imparts potency could also be accountable for interaction with the

6454
J. M. Bailey et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6452–6458
heme core of the 2D6 enzyme.26 Analysis of other non-aromatic
O O
S
N
groups in the series showed none had a comparable profile to the
pyrazole in 29 (cf. Table 1), so we initiated further investigation
aroundthesulfonamidecoretotryandimprovepotencyandefficacy
in the absence of the aromatic NH donor (Table 3).
N
NH
N
H
N
N
O
Compounds were prepared as NH benzazepines in either the n-
butylphenyl series cf. 18 or the pyridyl morpholine series cf. 29.
Sulfonamides 30 and 31 were only weakly active without the do-
nor pyrazole. Reversing the linker as in 32 had no effect on po-
tency, but switching from sulfonamide to amide resulted in a
total loss of activity as demonstrated in 33–36. Sulfone 37 showed
a modest increase in potency compared to sulfonamide 30, how-
ever replacement with the n-butylphenyl series gave 38, which
was 10-fold more potent than 5 on which it was based. This result
encouraged us to expand the SAR further around this aromatic sul-
fone template.
Potency:
Developability:
h-motilin R: pEC50 8.2 (1.0)
MW 468, clogP 2.4, CHI logD7.4 1.2
Efficacy:
Rabbit native tissue bath:
Aq. Sol. 371 µg/mL (pH 7.4)
CLi (mL/min/g): rat 3.8, hum 6.6
Emax 476% at 1µM
P450 enzyme inhibition (IC50 µM):
2D6 <1, Rest >8
Selectivity:
h-ghrelin R pEC50 <6,
5HT6 fpKi 6.2,
D2/D3 pKi <5.5 / 6.2
hERG pIC50 <4.8
Mouse PK (10 mg/kg oral) t 1.5 h;
½
T
max 2.0 h; Cmax 273 ng/mL.
Figure 4. Benzazepine compound 29.
Table 1
Agonist activity at motilin and ghrelin receptors for pyrazole analogues
O O
S
N R
N
H
Compound
R
h-MotilinR
pEC50 (IA)a
h-GhrelinR
pEC50 (IA)b
5
6
H
5.8 (0.8)
6.7 (0.8)
—
<6
7
8
5.7 (0.96)
<4.9
<6
—
O
NMe
O
9
<5.6
—
N
Me
10
11
12
<5.5
—
O
Me
Me
6.3 (0.7)
5.6 (0.9)
<5
<6
NH
S
S
O
13
14
7.3 (0.9)
8.1 (0.8)
<6
N
H
NH
8.4 (0.4)
N
NH
15
16
8.5 (0.8)
7.2 (0.7)
8.4 (0.6)
7.7 (0.5)
Me
N
NH
Me
Me
N
N
N
N
17
18
5.5 (0.7)
8.6 (0.7)
—
7.1 (0.7)
NH
a
IA refers to intrinsic activity compared to human motilin.
IA refers to intrinsic activity compared to human ghrelin.
b

J. M. Bailey et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6452–6458
6455
Table 2
Profile of compounds for replacement of the n-butylphenyl group
O O
S
N
N
N
R
H
NH
Compound
R
h-MotilinR
pEC50 (IA)
h-GhrelinR
pEC50 (IA)
5HT6
fpKi
D2 pKi binding
D3 pKi binding
c log P
P450 (IC50 lM)
19
20
<4.9
—
—
—
—
—
—
—
2.0
2.8
2D6 16
—
5.6 (0.8)
<6.0
21
5.1 (1.0)
—
—
—
—
2.9
2C9 2.5
2D6 7.9
NC
Cl
22
23
24
6.1 (0.9)
7.4 (0.7)
8.0 (0.9)
<5
—
—
—
3.8
4.3
4.7
—
—
Cl
7.1 (0.7)
5.8 (0.7)
8.2
6.9
6.4
6.2
7.0
7.5
Me
3A4, 2D6
<0.1
O
25
26
8.4 (1.0)
8.3 (1.2)
6.8 (0.6)
6.2 (0.7)
6.7
—
6.2
—
7.7
—
3.9
4.6
2D6 1.3
2D6 0.5
O
O
N
27
28
29
7.5 (0.8)
8.1 (1.0)
8.2 (1.0)
<5
<5
<6
7.8
6.8
6.2
<6.0
<6.1
<5.5
6.2
6.7
6.2
3.4
3.6
2.4
—
Me
S
2C9 0.4
2D6 0.2
N
O
N
2D6 0.2
N
Removal of the n-butyl group in 38 gave unsubstituted phenyl
sulfone 39 which was inactive at the motilin receptor (Table 4).
Addition of t-butyl or the fused naphthyl ring system 40 and 41 re-
stored some potency at the expense of lipophilicity. This early SAR
suggested a more linear group was preferred, and this was con-
firmed when a boost in activity came with the addition of the 4-
substituted biphenyls 42–44. In this way the sulfone SAR followed
that of the earlier sulfonamides (cf. Table 2). We were pleased to
see low microsomal clearance for the three biphenyls, although
the N-linked piperidine 52 performing best. We were surprised
to see that replacing this with 4-fluoroaniline gave a 20 nM com-
pound 53, 25-fold more potent than the ether analogue 49.
Two of the best compounds were tested in the rabbit native tis-
sue assay, with modest results; Compound 43 gave Emax 166% at
3 lM and 46 54% at 1 lM. Ultimately however all compounds suf-
fered the same fate—the more active compounds tended to be
more lipophilic, which correlated to high levels of inhibition at
CYP 2D6, and as such were not progressed further. This is clearly
illustrated by comparing piperidine 52 (c log P = 2.4, 2D6
they still showed sub-lM potency at CYP 2D6. It was felt that
the high c log P (P4) was a contributing factor here, so further
compounds were designed to raise the PSA and reduce c log P in
an effort to address this. Pleasingly, the pyridyl analogues 45 and
46 were equipotent with the best pyrazole sulfonamides 28 and
29. 4-F substitution seemed to offer the best profile, reducing
c log P to a reasonable level (3.3) and a suggestion of lower 2D6
inhibition. More polar acceptors such as CN on the biaryl group
were not well tolerated.
In an effort to raise the PSA further, addition of a polar linker be-
tween the pyridyl and 4-fluorophenyl rings, in the form of amide
48 or phenyl ether 49 resulted in a 100-fold drop in activity. This
effect was reversed somewhat with smaller alkyl ethers 50 and
51, suggesting a lack of space at this end of the ligand–receptor
complex. Smaller amine substituents were also tolerated, with
IC50 = 1.1 lM) with morpholine 37 (c log P = 1.1, 2D6 IC50 = 16 lM),
a marked difference for such a simple change. This would suggest
the earlier heme H-bonding proposal may not be involved, or at
least be the only binding mode within the CYP2D6 receptor for
these benzazepine ligands. More studies may be needed to evalu-
ate these findings further.
The synthesis of the benzazepine sulfonamides used standard
conditions beginning with sulfonylation of the known benzazepine
5427 using commercially available sulfonyl chlorides. Removal of
the Boc group and reductive amination then gave the final prod-
ucts. This chemistry is exemplified by the synthesis of the 4-n-
butylphenyl analogues (Scheme 1). The final step was a reductive
amination array (dimensions 1 ꢀ 60) utilizing borohydride resin
which facilitated the reaction work up. Purification was achieved

6456
J. M. Bailey et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6452–6458
Table 3
Effect of linker changes
NH
LINK
R
Compound
R
LINK
h-MotilinR
pEC50 (IA)
O
R S NH
O
O
N
30
31
32
33
34
35
36
37
38
5.8 (0.65)
5.6 (0.4)
5.6 (0.6)
<4.9
N
O
nBu
O
R S N
Me
O
O
R
N
N
N
N
N
N
HN S
O
N
N
N
N
N
N
O
O
O
O
O
O
NH
R
HN
R
<4.9
O
O
N
<4.9
R
O
Me
N
<4.9
R
Me
O
R S
O
O
R S
O
6.3 (0.8)
6.9 (1.0)
nBu
Table 4
Benzazepine sulfone SAR
O
S
O
R
NH
Compound
R
h-MotilinR
pEC50 (IA)
h-GhrelinR
pEC50
c log P
P450 2D6 (IC50
lM)
CLi rat (mL/min/g)
CLi human (mL/min/g)
39
40
41
42
43
44
45
<4.9
<6
<5
<5
<5
<5
<5
<6
1.9
3.8
3.1
4.6
4.0
4.1
3.9
—
—
—
5.5 (1.0)
5.9 (0.7)
7.7 (1.1)
7.9 (1.1)
7.6 (1.5)
8.1 (1.3)
—
—
—
—
—
—
<0.1
0.2
0.1
<0.1
<0.5
<1
1.1
<1
<1
<1
1.0
<1
Cl
F
F
F
Cl
N

J. M. Bailey et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6452–6458
6457
Table 4 (continued)
Compound
R
h-MotilinR
pEC50 (IA)
h-GhrelinR
pEC50
c log P
P450 2D6 (IC50
lM)
CLi rat (mL/min/g)
CLi human (mL/min/g)
F
46
47
48
49
50
51
52
53
37
8.3 (1.0)
6.8 (1.1)
5.7 (0.7)
6.3 (0.8)
6.8 (0.8)
7.4 (0.8)
7.2 (0.9)
7.7 (0.8)
6.3 (0.8)
<6
<6
—
3.3
2.6
2.8
3.3
2.7
3.3
2.4
3.8
1.1
0.6
—
<0.5
—
<1
—
N
NC
F
N
NH
O
—
—
—
N
F
<6
<6
<6
<6
<6
<6
1.7
1.6
—
—
—
O
N
—
—
O
N
—
—
O
N
N
N
1.1
0.3
16
—
—
F
<0.5
<1
<1
<0.5
N
N
H
N
O
N
SO2Cl
i
iii
O O
O O
NBoc
N R
N
+
S
S
N
nBu
H2N
N
H
R1
H
54
nBu
nBu
R = Boc
R = H
ii
Scheme 1. Reagents and conditions: (i) diisopropylethylamine, CH2Cl2, rt, 74%; (ii) trifluoroacetic acid, 1,3-dimethoxybenzene, CH2Cl2, rt, 99%; (iii) R1CHO, MP-BH(OAc)3
resin, THF/DMF, rt; PL-NCO resin; SCX cartridge; further purification as necessary, for example, mass directed auto purification using reverse phase HPLC.
using isocyanate scavenging resin and strong cation exchange car-
tridges. Compound purity was assessed at this point and further
purification was carried out as necessary, for example by mass di-
rected auto purification using reverse phase HPLC.
The methylene sulfone compounds were readily prepared using
sulfinate chemistry.28 Thus conversion of 6-chloro-3-pyr-
idinesulfonyl chloride to the sodium sulfinate salt, followed by
alkylation with the known bromide 5529 gave methylene sulfone
R
ii
iii
O
O
O
O
O
O
O
+
i
NBoc
NBoc
NBoc
NBoc
N R
Br
Br
S
S
S
Cl
N
Cl
N
N
N
R = SO2Cl
R = SO2Na
55
56
R = Boc
O
iv
37
R = H
SO2Na
+
v
vi
F
O
N R
S
Br
Br
55
57
R = Boc
vii
R = H 43
Scheme 2. Reagents and conditions: (i) Na2SO3, Na2HPO4, EtOH, H2O, 55 °C; (ii) nBu4N+Brꢁ, DME, 85 °C, 69% over two steps; (iii) morpholine, iPr2NEt, THF, DMF, 100 °C
(microwave), 81%; (iv) 4 M HCl/dioxan, DCM, rt, 75%; (v) nBu4N+Brꢁ, DME, 85 °C, 53%; (vi) 4-fluorophenyl boronic acid, Pd(PPh3)4, NaHCO3, toluene, EtOH, H2O, reflux, 86%;
(vii) 4 M HCl/dioxan, DCM, rt, 100%.

6458
J. M. Bailey et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6452–6458
14. Ray, W. A.; Murray, K. T.; Meredith, S.; Narasimhulu, S. S.; Hall, K.; Stein, C. M.
N. Eng. J. Med. 2004, 351, 1089.
15. Tack, J.; Peeters, T. Gut 2001, 49, 317.
16. Peeters, T. L. Neurogastroenterol. Motil. 2006, 18, 1.
17. Peeters, T. L. Curr. Opin. Investig. Drugs 2001, 2, 555.
56 in good yield (Scheme 2). Nucleophilic displacement under
thermal conditions followed by deprotection then gave com-
pounds such as morpholine 37 as shown. The biphenyl compounds
were prepared in a similar manner. Thus commercially available
sodium bromobenzenesulfinate and bromide 55 were reacted to
form sulfone 57. Suzuki coupling and deprotection gave biphenyl
compounds as exemplified by 43.30
In conclusion, we report here for the first time a series of small
molecule motilin receptor agonists, based on a chemically tractable
benzazepine sulfonamide or sulfone core. When compared to the
4-n-butylphenylsulfonamide compound 1, promising new leads
have displayed higher levels of potency, selectivity and efficacy
in a disease relevant tissue assay. Morpholinylpyridine compound
2930 additionally had a promising oral pharmacokinetic profile in
mice. Switching to methylene sulfone linkers gave good potency
in the absence of the pyrazole donor group, and had the positive
effect of reducing the MW to below 400.31 Further progression of
18. McCallum, R. W.; Cynshi, O. Aliment. Pharmacol. Ther. 2007, 26, 1121.
19. McCallum, R. W.; Cynshi, O. Aliment. Pharmacol. Ther. 2007, 26, 107.
20. (a) Heightman, T. D.; Conway, E.; Corbett, D. F.; MacDonald, G. J.; Stemp, G.;
Westaway, S. M.; Celestini, P.; Gagliardi, S.; Riccaboni, M.; Ronzoni, S.; Vaidya,
K.; Butler, S.; McKay, F.; Muir, A.; Powney, B.; Winborn, K.; Wise, A.; Jarvie, E.
M.; Sanger, G. J. Bioorg. Med. Chem. Lett. 2008, 18, 6423; (b) Westaway, S. M.;
Brown, S. L.; Conway, E.; Heightman, T. D.; Johnson, C. N.; Lapsley, M. K.;
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22. For details of the motilin receptor agonist FLIPR assay, see Ref. 20a.
23. For details of the rabbit isolated gastric antrum native tissue assay, see: Jarvie,
E. M.; North Laidler, V. J.; Corcoran, S.; Bassil, A.; Sanger, G. J. Brit. J. Pharmacol.
2007, 150, 455.
the series was precluded due to the sub-lM CYP 2D6 activity.
However their nM potency makes them valuable tools for further
investigation, and provide yet more evidence that small molecule
agonists of peptide GPCRs are a realisable goal.
Acknowledgements
24. For details of the ghrelin receptor agonist assay, see: Heightman, T. D.; Scott, J.
S.; Longley, M.; Bordas, V.; Dean, D. K.; Elliott, R.; Hutley, G.; Witherington, J.;
Abberley, L.; Passingham, B.; Berlanga, M.; de los Frailes, M.; Wise, A.; Powney,
B.; Muir, A.; McKay, F.; Butler, S.; Winborn, K.; Gardner, C.; Darton, J.; Campbell,
C.; Sanger, G. Bioorg. Med. Chem. Lett. 2007, 17, 6584.
25. For representative procedures for determining P450 inhibition and intrinsic
clearance, see: Michell, F.; Bonanomi, G.; Blaney, F. E.; Braggio, S.; Capelli, A.
M.; Checchia, A.; Curcuruto, O.; Damiani, F.; Di Fabio, R.; Donati, D.; Gentile, G.;
Gribble, A.; Hamprecht, D.; Tedesco, G.; Terreni, S.; Tarsi, L.; Lightfoot, A.;
Stemp, G.; MacDonald, G.; Smith, A.; Pecoraro, M.; Petrone, M.; Perini, O.; Piner,
J.; Rossi, T.; Worby, A.; Pilla, M.; Valerio, E.; Griffante, C.; Mugnaini, M.; Wood,
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C.; Hagan, J.; Heidbreder, C. J. Med. Chem. 2007, 50, 5076.
We are grateful to Masato Iwaya for generating the in vivo PK
data and to Emma V. Edgar, Laurie J. Gordon, Abir A. Khazragi
and Rekha Pindoria for generating the 5HT6, D2 and D3 data.
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J 2.4 Hz), 7.71 (1H, dd, J 9.2, 2.4 Hz), 7.56 (1H, d, J 2.0 Hz), 6.91–6.95 (1H, m),
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(1H, s), 7.91 (2H, d, J 8 Hz), 7.84–7.80 (4H, m), 7.37 (2H, app. t, J 8 Hz), 7.16 (1H,
d, J 8 Hz), 7.05–7.01 (2H, m), 4.66 (2H, s), 3.18–2.98 (8H, m). MS: (ES+) 396
(MH+).
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