Discovery, oral pharmacokinetics and in vivo efficacy of a highly selective 5-HT4 receptor agonist: Clinical compound TD-2749

Article abstract of DOI:10.1016/j.bmcl.2012.05.034

Further application of our multivalent approach to drug discovery directed to 5-HT₄ receptor agonists is described. Optimization of the linker and secondary binding amine in the indazole-tropane primary binding group series, for binding affinity and functional potency at the 5-HT₄ receptor, selectivity over the 5-HT₃ receptor, oral pharmacokinetics, and in vivo efficacy in models of GI motility, resulted in the identification of clinical compound TD-2749.

Full text of DOI:10.1016/j.bmcl.2012.05.034

Bioorganic & Medicinal Chemistry Letters 22 (2012) 4849–4853
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery, oral pharmacokinetics and in vivo efficacy of a highly selective 5-HT4
receptor agonist: Clinical compound TD-2749
⇑
Daniel D. Long , Scott R. Armstrong, David T. Beattie, Seok-Ki Choi, Paul R. Fatheree,
Roland A. L. Gendron, Adam A. Goldblum, Patrick P. Humphrey, Daniel G. Marquess,
Jeng-Pyng Shaw, Jacqueline A. M. Smith, S. Derek Turner, Ross G. Vickery
Theravance, Inc., 901 Gateway Blvd, South San Francisco, CA 94080, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Further application of our multivalent approach to drug discovery directed to 5-HT4 receptor agonists is
described. Optimization of the linker and secondary binding amine in the indazole-tropane primary bind-
ing group series, for binding affinity and functional potency at the 5-HT4 receptor, selectivity over the 5-
HT3 receptor, oral pharmacokinetics, and in vivo efficacy in models of GI motility, resulted in the identi-
fication of clinical compound TD-2749.
Received 9 April 2012
Revised 5 May 2012
Accepted 8 May 2012
Available online 15 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
5-HT4 receptor agonist
Multivalent approach
TD-2749
GI motility
Alzheimer’s
The 5-HT4 receptor belongs to the superfamily of seven-trans-
membrane G protein-coupled receptors (GPCRs) and is an attrac-
tive target for drug discovery due to its potential role in many
central and peripherally mediated disorders (irritable bowel syn-
drome,1 gastroparesis,2 Alzheimer’s disease,3 arrhythmia4). In par-
ticular, activation of the 5-HT4 receptor has been demonstrated
both preclinically and clinically to promote gastrointestinal (GI)
motility. The peristaltic reflex describes the synchronized contrac-
tion and relaxation of GI smooth muscle resulting in the propulsion
of luminal contents and is dependent on increases in neurotrans-
mission due to 5-HT4 receptor activation on intrinsic primary affer-
ent neurons, interneurons and motor neurons.5 In addition,
agonism of 5-HT4 receptors on colonic circular smooth muscle cells
and on enterocytes promotes a direct relaxant effect and fluid
secretion, respectively, further facilitating GI transit.6
Three 5-HT4 receptor agonists have been approved for the treat-
ment of GI functional disorders, Figure 1. Cisapride (PropulsidÒ) (1)
and tegaserod (ZelnormÒ) (2) were frequently prescribed to treat
upper and lower GI disorders of reduced motility, respectively,
although their clinical efficacy in many patients was possibly re-
duced due to significant activity at other 5-HT receptor subtypes.7
Cisapride (1) is associated with an increased risk of mortality as a
consequence of inhibition of the human ether-a-go-go-related
gene (hERG) potassium ion channel.8 Tegaserod (2) is also associ-
ated with cardiovascular concerns, potentially as a result of its
interactions at non-5-HT4 serotonergic receptors.9 However, two
recent epidemiological studies failed to support the purported in-
creased risk of serious ischemic cardiovascular events with tegas-
erod.10 Marketing in the US of both cisapride (1) and tegaserod
(2) has been suspended although the clinical prescription of both
drugs is now possible, but highly restricted.11
Drug discovery efforts to identify novel selective 5-HT4 receptor
agonists have focused on approaches to improve both clinical effi-
cacy and patient safety.12 Prucalopride (ResolorÒ) (3) was recently
approved in Europe for the treatment of women with chronic idi-
opathic constipation who have not responded adequately to laxa-
tives and represents a next generation, highly selective 5-HT4
receptor agonist.13 We recently reported our multivalent approach
to the design and discovery of selective 5-HT4 receptor agonists
such as THRX-194556 (4), Figure 2.14 Key to the strategy was the
exploration of primary and secondary binding groups and the con-
necting linker, as represented by the proposed 5-HT4 receptor ago-
nist pharmacophore shown in Figure 2. From the initial screening
study, combining the quinolone-tropane primary binding group
of THRX-194556 (4) with amine-based secondary binding groups
afforded high affinity 5-HT4 receptor agonists, with high selectivity
over the 5-HT3 receptor, somewhat independent of linker length
and composition. Additional optimization of the amine-based
secondary binding group and the linker focused on ‘drug-likeness’
features, specifically permeability in the Caco-2 assay, rat in vivo
oral pharmacokinetic data and hERG potassium ion channel
⇑
Corresponding author.
E-mail address: dlong@theravance.com (D.D. Long).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.05.034

4850
D. D. Long et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4849–4853
F
O
O
N
OMe
HN
Cl
O
N
O
HN
N
N
H
NH
Cl
N
H
OMe
H2N
MeO
OMe
H2N
N
H
Prucalopride, 3
Tegaserod, 2
Figure 1. 5-HT4 receptor agonists to have reached the market.
Cisapride, 1
inhibition. It was found that the best balance of these properties
was associated with a low pKa of the secondary binding group
resulting in identification of THRX-194556 (4).15 As a further
example of our multivalent approach to drug discovery16 we
herein describe the optimization and characterization of the
indazole-tropane primary binding group to afford clinical
compound TD-2749 (14).
2-propanol linked compounds 6–8a and 10a (Kp >19) compared
favorably with the previously optimized THRX-194556 (4),
(Kp = 14). However, for the primary sulfonamide substituted piper-
idine 9a permeability was low (Kp = 1) possibly due to the H-bond
donating character of this motif. Inhibition of the hERG potassium
ion currents for compounds 6–8a and 10a was very dependent on
the secondary binding amine although there did not appear to be a
relationship between channel inhibition and cpKa2. The piperidine
containing compound 6a exhibited 62% inhibition of the channel at
Results and Discussion
3 lM. The isopropyl-methylamine 7a and 2-methoxypyrolidine 8a
compounds displayed moderate hERG inhibition (29–33%) and the
piperazine sulfonamide 10a showed encouragingly weak inhibi-
tion (4%) similar to THRX-194556 (4), containing this same motif.
On the basis of the promising potency, good in vitro permeabil-
ity and weak hERG inhibition observed with compound 10a its sin-
gle enantiomers 11 and 12 were synthesized and profiled, Table 1,
Scheme 2. Following the same trend as observed with THRX-
194556 (4), the (S)-enantiomer 12 was found to have significantly
higher 5-HT4 receptor affinity and functional potency, and selectiv-
ity over the 5-HT3 receptor, relative to the (R)-enantiomer 11. The
oral pharmacokinetics (PK) in rats of the (S)-enantiomer 12 was
determined and found to be comparable to that of the previously
identified THRX-194556 (4), Table 2. The binding affinity for the
indazole-tropane compound 12 was greater than that for THRX-
194556 (4), although the functional potency was equal.
Schemes 1–3 detail the preparation of the compounds de-
scribed in this communication. From the previously reported initial
screen the indazole-tropane primary binding group 5, Scheme 1,
exhibited high binding affinity (pKi = 7.2) and functional potency
(pEC50 = 7.4) along with high intrinsic activity (IA = 94% of the
maximum response achieved by 5-HT in a cAMP accumulation as-
say) at the human recombinant 5-HT4 receptor.14 However, it also
had high binding affinity for the human recombinant 5-HT3 recep-
tor (selectivity <1). A variety of amine derived secondary binding
groups attached to the indazole-tropane core by either the previ-
ously optimized 2-propanol, or simple hexyl linkers, were first
investigated, Table 1, Scheme 1.
As expected from the previously reported SAR with the quino-
lone-tropane primary binding group,14 addition of the amine de-
rived secondary binding groups to the indazole-tropane
5
Since it had been previously concluded that lowering the cpKa1
and cpKa2 of the propyl linker by introduction of the 2-hydroxy
group was beneficial to the overall profile, the effect of further
reducing the basicity by using an ethyl linker was explored. This
was significantly deleterious to 5-HT4 receptor binding in the pre-
viously reported case of the quinolone-tropane series.14 The ethyl
linked piperazine-sulfonamide and the less basic acetyl-piperazine
analogues, 13 and 14 respectively, were both prepared, Table 1,
Scheme 3.17 Relative to the 2-(S)-propanol linked compound 12,
both ethyl-linked analogues had lower 5-HT4 receptor binding
affinity and functional potency although microsome stability and
hERG inhibition properties remained favorable, whilst permeabil-
ity was improved. Significantly, the binding selectivity over the
5-HT3 receptor was reduced for the piperazine sulfonamide ana-
logue 13 relative to the acetyl-piperazine 14 (110-fold and 980-
fold, respectively). Both compounds 13 and 14 were independently
dosed orally to rats to see if the in vitro permeability increase
increased both the binding affinity (pKi >8.4) and the functional
potency (pEC50 >7.9) at the 5-HT4 receptor. The observed trend
was that the binding affinity was highest for the hexyl linked com-
pounds (6–10b vs 6–10a, respectively) which correlated with the
increased cpKa1 and cpKa2. This same trend was not apparent with
regards to the functional potency of the compounds. In fact whilst
all the compounds 6–10a,b had higher binding affinity than the
quinolone-tropane THRX-194556 (4), they all had lower functional
potency. The selectivity of the compounds in this study over the 5-
HT3 receptor was very dependent on the linker. For each of the
amine secondary binding groups attached via the 2-propanol
linker (compounds 6–10a) excellent selectivity of >3000-fold was
observed. In contrast, the selectivity was <25-fold for all the
hexyl-linked compounds 6–10b and as a consequence these were
not advanced to subsequent screening assays. Stability was high
for all the compounds 6–10a in the rat liver microsome (RLM) as-
say. The permeability (as measured by the Caco-2 assay) for the
Secondary Binding Group
Primary Binding Group
Primary Binding Group
Secondary
N
N
O
O
O
N
Binding
Group
OH
N
SO2Me
N
H
N
H
H
Aromatic
System
Linker
N
Linker
THRX-194556, 4
Figure 2. Proposed 5-HT4 receptor agonist pharmacophore.

D. D. Long et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4849–4853
4851
N
R1
O
(i)
or
R1 Secondary Binding Amines:
OH
N
H
(ii)
H
N
N
N
N
N
N
8
6-10a
MeO
NH
O
6
7
N
H
H
N
N
N
R1
O
N
(iii)
4
NHSO2Me
N
5
N
H
SO2Me
H
N
N
9
10
6-10b
Scheme 1. Reagents and conditions: (i) Amines 6–8 and 10, 1,3-dibromo-2-propanol, DIPEA, MeOH, 65 °C; (ii) (a) rac-epibromohydrin, DIPEA, EtOH, (b) amine 9, EtOH, 90 °C;
(iii) amines 6–10, 1,6-dibromohexane, DIPEA, MeOH, 65 °C.
(i)
(ii)
HN
N
N
N
O
O
N
N
OH
N
SO2Me
SO2Me
SO2Me
N
H
H
N
N
11-(R)-OH
12-(S)-OH
Scheme 2. Reagents and conditions: (i) For 11: (a) (R)-epichlorohydrin, DIPEA, EtOH, (b) NaOH, THF, H2O; for 12: (a) (S)-epichlorohydrin, EtOH, (b) NaOH, THF, H2O, 0 °C (ii) 5,
toluene, 98 °C.
R1
N
OH
OH
N
NH
N
N
O
O
(ii)
O
(i)
N
H
N
H
N
H
H
H
H
N
N
N
N
N
N
13: R1=SO Me
TD-2749 (14): 2R1=Ac
5
Scheme 3. Reagents and conditions: (i) (a) Dimethoxyacetaldehyde in tBuOMe, DIPEA, CH2Cl2 then NaBH(OAc)3, (b) 6M HCl, 70 °C; (ii) For 13: 1-methanesulfonyl-piperazine,
NaBH(OAc)3, DIPEA, CH2Cl2; For 14: 1-acetyl-piperazine, NaBH(OAc)3, DIPEA, CH2Cl2.
translated into improved oral exposure, Table 2. Whilst pipera-
zine–sulfonamide compound 13 had a similar rat PK profile to its
2-(S)-propanol analogue 12, the acetyl piperazine compound 14
was significantly improved as reflected by increased Cmax, AUC
and overall %F.
Due to its balanced overall profile and structural diversity
relative to both the quinolone-tropane and indazole-tropane 2-
(S)-propanol-piperazine sulfonamides 4 and 12, the ethyl linked
acetyl-piperazine 14 was selected for further evaluation.
With respect to selectivity over other 5-HT receptors,
compound 14 displayed less than 50% inhibition of 5-HT1A,B,D, 5-
HT2A,B,C, 5-HT3A, 5-HT5A, 5-HT6 and 5-HT7 at a concentration of
europium labeled GTP assay (pEC50 = 8.2; IA = 57%). These results,
reflecting a partial agonist property of compound 14 were in con-
trast to tegaserod and THRX-194556 (4) which exhibited good po-
tency and high intrinsic activity in these assays. [pEC50 = 9.0, 8.7,
7.8; IA = >100%, 99%, 71%, respectively for tegaserod; pEC50 = 9.4,
8.7, 8.4; IA = 94%, >100%, >100%, respectively for THRX-194556
(4)].
Compound 14 produced a concentration-dependent contraction
of the guinea pig isolated colonic longitudinal muscle/myenteric
plexus preparation. The potency of 14 (pEC50 = 8.0) was similar
to that of 5-HT and tegaserod (2) (pEC50 = 8.0 and 8.2, respec-
tively). However, 14 had an intrinsic activity greater than that of
tegaserod (85% vs 65% of the 5-HT maximum, respectively). Con-
sidering the wealth of literature demonstrating that 5-HT4 receptor
activation results in contraction of this smooth muscle prepara-
tion,18,19 and the presence of antagonists of 5-HT1, 5-HT2 and 5-
HT3 receptors in these isolated tissue experiments, the observed
activity of 14 was concluded to represent 5-HT4 receptor
activation.
10 lM. In contrast, tegaserod displays relatively high binding
affinity (pKi >7.0) at 5-HT1D, 5-HT2A,C and 5-HT7 receptors, and
has particularly high binding affinity (pKi >8.7) for the 5-HT2B
receptor. Cisapride is only 20-fold selective for the 5-HT4 receptor
relative to the 5-HT3 receptor.
The potency and intrinsic activity of compound 14 in the func-
tional cAMP accumulation assay were determined to be high
(pEC50 = 8.6; IA = 83%) using a cell line expressing the 5-HT4(c)
receptor at 100-fold physiological levels. However, when a cell line
expressing the 5-HT4(c) receptor at 10-fold physiological levels was
used the potency (pEC50 = 8.0) was similar but the intrinsic activity
was more modest (IA = 53%). Partial agonist activity was also
observed in a 5-HT4(c) receptor-mediated exchange of GDP for
To characterize the in vivo activity of 14, digital sonomicrome-
try was used to monitor 5-HT4 receptor-mediated esophageal
relaxation in the anesthetized rat.20 This method provided a novel
and sensitive means to demonstrate 5-HT4 receptor agonist-medi-
ated changes in endogenous esophageal tone. Compound 14 pro-
duced a dose-dependent, 5-HT4 receptor-mediated relaxation of

4852
D. D. Long et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4849–4853
Table 1
c
Compound Linker: 2-propanol
5-HT4 pKIa
Selectivity 5-HT4 pEC50
vs 5-HT3
5-HT4 IAd
cpKa1e cpKa2e RLM t1/2
Caco-2 Kp
hERG %
(1 Â 10À6 cm/s)
inhibitionf
b
(a) hexyl (b) ethyl (c)
(min)
Cisapride
Tegaserod
4
5
—
—
(S)-a
—
a
b
a
b
a
b
a
b
a
b
(R)-a
(S)-a
c
7.0
8.4
7.9
7.2
8.7
9.0
8.4
9.0
8.4
9.1
8.6
8.8
8.4
8.6
8.1
8.6
7.9
8.0
20
7.7
9.0
9.4
7.4
8.7
8.6
8.3
8.3
8.6
9.1
9.2
8.8
9.1
7.9
9.1
9.4
8.4
8.6
117
115
94
94
85
102
78
92
108
117
93
91
95
75
94
86
88
83
—
—
10.0
—
—
—
9.0
—
47
—
100
33
4
580
7400
<1
13000
12
6300
23
3000
14
19000
4.3
7300
3.6
240
23000
110
980
>90
>90
—
>90
—
>90
—
75
—
>90
—
>90
—
>90
>90
>90
>90
11
14
—
30
—
26
—
48
—
—
62
—
29
—
33
—
—
—
4
—
7
7
9
9
6a
6b
7a
7b
8a
8b
9a
9b
10a
10b
11
12
13
14
10.0
10.9
10.3
10.9
10.0
10.9
10.0
11.2
10.0
11.1
10.0
10.0
10.4
10.4
7.5
10.6
8.6
10.0
7.7
10.1
8.1
10.9
9.0
10.9
9.0
9.0
4.6
7.2
1
—
19
—
18
19
31
31
c
a
5-HT4 receptor binding pKi values were determined using a [3H]-GR113808 radioligand binding assay with membranes prepared from HEK-293 cells stably-transfected
with human recombinant 5-HT4(c) receptor splice variant.
b
5-HT3 receptor binding pKi values were determined with a [3H]-GR65630 radioligand binding assay with membranes prepared from HEK-293 cells stably-transfected
with human 5-HT3A receptor and selectivity for the 5-HT4 receptor type with respect to the 5-HT3 receptor type was calculated as the ratio Ki(5-HT3A)/Ki(5-HT4(c)).
c
pEC50 values were determined using whole-cell cAMP accumulation studies in HEK-293 cells stably-transfected with the human recombinant 5-HT4(c) receptor splice
variant.
d
Maximum compound-evoked response (minus basal) expressed as a percentage of the maximum response evoked by 5-HT.
Calculated pKa was calculated with the pKalc 3.2 prediction module of Pallas system (CompuDrug Chemistry, Ltd, Hungary).
Inhibition of hERG potassium ion currents was determined at a concentration of 3 lM using Chinese Hamster Ovary (CHO) cells stably-expressing hERG potassium
e
f
channels.
Table 2
%Fb
a
Compound
Linker: 2-propanol (a) ethyl (c)
Cmax
(
lg/mL)
AUC(0–t)
(l
g h/mL)
t1/2 (h)
4
(S)-a
(S)-a
c
0.031
0.035
0.099
0.254
0.20
0.24
0.26
0.73
5.2
7.4
1.8
3.2
20
36
48
>100
12
13
14
c
a
Pharmacokinetic properties were evaluated in male Sprague–Dawley rats dosed with test compounds via oral gavage (PO) at a dose of 5 mg/kg, n = 3.
F = Oral bioavailability.
b
the esophagus, following either intravenous (Fig. 3) or intraduode-
nal administration (data not shown). Following intravenous
administration, the rank order of potencies was tegaserod > 14 >
cisapride. The mean ED50 values for the relaxation response medi-
ated by intravenous tegaserod, 14 and cisapride were 10.6, 37.8
In the guinea pig colonic transit model, 14 (0.3 and 3.0 mg/kg
sc) produced a statistically significant decrease in the colonic tran-
sit time of carmine red dye relative to vehicle treated animals.21
Following subcutaneous administration, prokinetic activity was
evident when the distance traveled by the dye was measured
and 141.6 lg/Kg, respectively.
0.25
0.20
0.15
0.10
0.05
0.00
-0.05
125
Compound 14
Tegaserod
100
75
50
Compound 14
Tegaserod
Cisapride
*
*
25
0.01
0.1
1
10
100
1000 10000
0.1
1
10
Dose (µg/kg iv)
Subcutaneous dose (mg/kg)
Figure 3. Relaxation of rat esophagus following intravenous dosing of compound
14.
Figure 4. Guinea pig colonic transit following subcutaneous dosing of compound
14.

D. D. Long et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4849–4853
4853
7. (a) Kellow, J. E.; Cowan, H.; Shuter, B.; Riley, J. W.; Lunzer, M. R.; Eckstein, R. P.;
Höschl, R.; Lam, S.-K. Aliment. Pharmacol. Ther. 1994, 9, 153; (b) Evans, B. W.;
Clark, W. K.; Moore, D. J.; Whorwell, P. J. Cochrane Database Syst. Rev. 2004, 141,
44.
8. Mohammad, S.; Zhou, Z.; Gong, Q.; January, C. T. Am. J. Physiol. 1997, 273,
H2534.
9. De Maeyer, J. H.; Lefebvre, R. A.; Schuurkes, J. A. J. Neurogastroenterol. Motil.
2008, 20, 99.
10. (a) Anderson, J. L.; May, H. T.; Bair, T. L.; Muhlestein, J. B.; Horne, B. D.;
Carlquist, J. F. J. Cardiovasc. Pharmacol. Ther. 2009, 14, 170; (b) Loughlin, J.;
Quinn, S.; Rivero, E.; Wong, J.; Huang, J.; Kralstein, J.; Earnest, D. L.; Seeger, J. D.
J. Cardiovasc. Pharmacol. Ther. 2010, 15, 151.
60 min later (data not shown), or when the time for excretion of
the first fecal pellet containing the marker was recorded, Figure 4.
In this assay, 14 appeared to have superior potency to tegaserod,
although tegaserod did not achieve a statistically significant in-
crease in colonic transit at any of the doses tested.
Upon completion of the preclinical profiling including confirma-
tion of the impressive in vivo efficacy of compound 14 in additional
species it was designated as a development candidate, TD-2749
and advanced to human clinical trials.
11. (a) http://propulsid-lap.com/; (b) http://www.fda.gov/Drugs/DrugSafety/
PostmarketDrugSafetyInformationforPatientsandProviders/ucm103223.htm
12. Manabe, N.; Wong, B. S.; Camilleri, M. Exp. Opin. Invest. Drugs 2010, 19, 765.
13. Camilleri, M.; Kerstens, R.; Rykx, A.; Vandeplassche, L. N. Engl. J. Med. 2008, 358,
2344.
14. McKinnell, R. M.; Armstrong, S. R.; Beattie, D. T.; Choi, S.-K.; Fatheree, P. R.;
Gendron, R. A. L.; Goldblum, A.; Humphrey, P. P.; Long, D. D.; Marquess, D. G.;
Shaw, J. P.; Smith, J. A. M.; Turner, S. D.; Vickery, R. G. J. Med. Chem. 2009, 52,
5330.
Conclusions
Additional application of the previously reported multivalent
approach to drug discovery towards 5-HT4 receptor agonists re-
sulted in the identification of TD-2749, which was selected as a
development candidate. TD-2749 is a potent and highly selective
5-HT4 receptor agonist in vitro with robust in vivo GI activity
and an attractive oral pharmacokinetic profile.
15. This compound advanced to rodent safety studies but further development
was halted due to the significant finding of a reduction in body weight gain
upon repeat dosing over 7 d.
16. (a) Long, D. D.; Aggen, J. B.; Christensen, B. G.; Judice, J. K.; Hegde, S. S.; Kaniga,
K.; Krause, K. M.; Linsell, M. S.; Moran, E. J.; Pace, J. L. J. Antibiot. 2008, 61, 595;
(b) Choi, S.-K.; Green, D.; Ho, A.; Klein, U.; Marquess, D.; Taylor, R.; Turner, S. D.
J. Med. Chem. 2008, 51, 3609; (c) Hughes, A. D.; Chin, K. H.; Dunham, S. L.;
Jasper, J. R.; King, K. E.; Lee, T.-W.; Mammen, M.; Martin, J.; Steinfeld, T. Bioorg.
Med. Chem. Lett. 2011, 21, 1354; (d) Jacobsen, J. R.; Choi, S.-K.; Combs, J.;
Fournier, E. J. L.; Klein, U.; Pfeiffer, J. W.; Thomas, R.; Yu, C.; Moran, E. J. Bioorg.
Med. Chem. Lett. 2012, 221, 1213.
Acknowledgments
The authors would like to thank Dr. Murray McKinnell and Dr.
Sharath Hegde from Theravance, Inc. for their assistance in review-
ing this article and Shanti Amagasu for electrophysiology work.
17. Complete syntheses of compounds 13 and 14 are described in: Marquess, D.;
Choi, S.-K.; Fatheree, P. R.; Gendron; R.; Goldblum, A. A.; Long, D. D.; Turner, S.
D.; Liu, J. U.S. Patent 8,044,045, 2011.
References and notes
18. Briejer, M. R.; Bosmans, J. P.; Van Daele, P.; Jurzak, M.; Heylen, L.; Leysen, J. E.;
Prins, N. H.; Schuurkes, J. A. J. Eur. J. Pharmacol. 2001, 423, 71.
19. Wardle, K. A.; Sanger, G. J. Br. J. Pharmacol. 1993, 110, 1593.
20. Armstrong, S. R.; McCullough, J. L.; Beattie, D. T. J. Pharm. Tox. Meth. 2006, 53,
198.
21. Beattie, D. T.; Armstrong, S. R.; Shaw, J. P.; Marquess, D.; Sandlund, C.; Smith, J.
A.; Taylor, J. A.; Humphrey, P. P. Naunyn Schmiedebergs Arch. Pharmacol. 2008,
378, 139.
1. (a) Sanger, G. J. Neurogastroenterol. Motil. 1996, 8, 319; (b) Tonini, M.; Fabio, P.
Dig. Dis. 2006, 24, 59.
2. Bouras, E. P.; Camilleri, M.; Burton, D. D.; Mckinzie, S. Gut 1999, 44, 682.
3. Maillet, M.; Robert, S. J.; Lezoualc’h, F. Curr. Alzheimer Res. 2004, 1, 79.
4. Kaumann, A. J. Trends Pharmacol. Sci. 1994, 15, 451.
5. (a) Jin, J. G.; Foxx-Orenstein, A. E.; Grider, J. R. J. Pharmacol. Exp. Ther. 1999, 288,
93; (b) Gershon, M. D.; Tack, J. Gastroenterol. 2007, 132, 397.
6. (a) Hansen, M. B.; Skadhauge, E. Comp. Biochem. Physiol. 1997, 118, 283; (b)
Hillier, K.; Tam, F. S. F.; Bunce, K. T.; Grossman, C. Br. J. Pharmacol. 1994, 112,
102P.