Discovery, oral pharmacokinetics and in vivo efficacy of velusetrag, a highly selective 5-HT4 receptor agonist that has achieved proof-of-concept in patients with chronic idiopathic constipation

Article abstract of DOI:10.1016/j.bmcl.2012.08.051

Utilization of Theravance's multivalent approach to drug discovery towards 5-HT₄ receptor agonists with a focus on identification of neutral (non-charged at physiological pH) secondary binding groups is described. Optimization of a quinolone-tr

Full text of DOI:10.1016/j.bmcl.2012.08.051

Bioorganic & Medicinal Chemistry Letters 22 (2012) 6048–6052
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 velusetrag, a
highly selective 5-HT4 receptor agonist that has achieved proof-of-concept
in patients with chronic idiopathic constipation
⇑
Daniel D. Long , Scott R. Armstrong, David T. Beattie, Seok-Ki Choi, Paul R. Fatheree,
Roland A. L. Gendron, Daniel Genov, Adam A. Goldblum, Patrick P. Humphrey, Lan Jiang,
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, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Utilization of Theravance’s multivalent approach to drug discovery towards 5-HT4 receptor agonists with
a focus on identification of neutral (non-charged at physiological pH) secondary binding groups is
described. Optimization of a quinolone-tropane primary binding group with a chiral 2-propanol linker
to a range of neutral secondary binding group motifs, 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, afforded velusetrag (TD-5108). Velusetrag has achieved proof-of-concept in patients with
chronic idiopathic constipation.
Received 20 July 2012
Accepted 13 August 2012
Available online 21 August 2012
Keywords:
5-HT4 receptor agonist
Multivalent approach
Velusetrag
Ó 2012 Elsevier Ltd. All rights reserved.
TD-5108
GI motility
Alzheimer’s
Drug discovery efforts to identify novel selective 5-HT4 receptor
agonists have intensified in recent years following the approval
and subsequent marketing suspension of cisapride (PropulsidÒ)
(1) and tegaserod (ZelnormÒ) (2), Figure 1. More recently prucalo-
pride (ResolorÒ) (3) was approved in Europe for the treatment of
women with chronic idiopathic constipation who have not re-
sponded adequately to laxatives. In contrast to cisapride and tegas-
erod, prucalopride has a high degree of selectivity for the 5-HT4
receptor over other 5-HT or non-5-HT receptors.1 All three of these
agents have been prescribed to patients for the treatment of GI
functional disorders. In addition, preclinical evidence that 5-HT4
receptor agonists may be of benefit for both the symptomatic
and disease-modifying treatment of cognitive disorders is substan-
tial2 and clinical benefit in a small Phase 2 study in Alzheimer’s dis-
ease patients was reported with the selective 5-HT4 receptor
partial agonist, PRX-03140.3
pharmacophore in Figure 2. Ultimately it was found that in the
indazole–tropane series, short linkers (<3 linear atoms) provided
the best balance of high affinity 5-HT4 receptor agonism, and good
selectivity over the 5-HT3 receptor. In addition, modulation of the
pKa of the secondary binding group was investigated to maximize
rat in vivo oral pharmacokinetic properties. Since it was deter-
mined that lowering the pKa correlated with a favorable overall
profile of the 5-HT4 receptor agonist compounds, we decided to re-
visit the concept of a neutral secondary binding group that would
not be charged at physiological pH. In our original paper detailing
the discovery of THRX-194556 (5) we reported that in the quino-
lone–tropane series, neutral-alkyl, hydroxyl and phthalimide sec-
ondary binding groups were generally not as high binding
affinity or as potent compared with corresponding amine-based
secondary binding groups such as the piperazine–sulfonamide of
THRX-194556 (5), over a range of linker lengths.6 Regardless, we
wanted to investigate whether we could optimize a neutral sec-
ondary binding group using the short linker SAR we had subse-
quently determined, combined with key interactions that likely
contribute to some of the more potent amine-based secondary
binding groups. We herein describe application of this approach
to the quinolone–tropane primary binding group to afford the clin-
ical compound velusetrag (15).
In our earlier paper4 we described the further application of
Theravance’s multivalent approach to drug discovery5 directed to
5-HT4 receptor agonists, through the elaboration of an indazole–
tropane primary binding group, resulting in the identification of
clinical compound TD-2749 (4). The key element of the approach
was the optimization of both an amine-based secondary binding
group and the linker motif according to the 5-HT4 receptor agonist
Schemes 1–3 detail the preparation of the compounds
described in this communication. We initially chose to retain both
the quinolone–tropane primary binding group6 and 2-propanol
⇑
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.2012.08.051

D. D. Long et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6048–6052
6049
F
O
O
N
OMe
HN
Cl
H2N
O
N
O
HN
N
N
H
NH
Cl
N
H
MeO
OMe
H2N
OMe
N
H
Prucalopride, 3
Tegaserod, 2
Figure 1. 5-HT4 receptor agonists to have reached the market.
Cisapride, 1
Figure 2. Theravance 5-HT4 receptor agonists.
R1
N
H
N
NH2
O
N
N
O
O
(iii)
OH
OH
N
H
H
H
H
(i)
N
O
N
7a
8-13a
NH
O
O
N
H
H
R1
N
N
N
O
NH
N
O
O
(ii)
(iii)
OH
OH
N
H
N
H
6
H
H
N
O
N
7b
8-13b
R1 Secondary Binding Neutral Groups:
O
9
O
O
O
O
O
8
S
O
NH2
N
H
N
O
10
11
12
13
Scheme 1. Reagents and conditions: (i) (a) N-(2,3-epoxypropyl)-2-phthalimide, DIPEA, EtOH, 80 °C, (b) hydrazine, EtOH, 80 °C; (ii) (a) rac-epibromohydrin, EtOH, 80 °C, (b)
MeNH2 (41% in H2O), EtOH, 80 °C; (iii) 8a: AcOH, PyBOP, DIPEA, DMF; 8b: AcCl, DIPEA, DMF; 9a,b: (CH3)3SiNCO, DIPEA, DMF; 10a,b: CH3NCO, DIPEA, DMF; 11a,b:
(CH3)2NCOCl, DIPEA, DMF; 12a,b: CH3OCOCl, DIPEA, DMF; 13a,b: MsCl, DBU, DCM.
linker (initially exploring the racemic form) of THRX-194556 (5)
and investigated functionalization of both a terminal primary
amine precursor 7a and a terminal secondary N-methyl amine pre-
cursor 7b to afford compounds 8–13a (NH series) and 8–13b (NMe
series), respectively. Simple amide, carbamate, urea and sulfon-
amide neutral secondary binding group compounds were pre-
pared, Table 1, Scheme 1.
Encouragingly a number of compounds from both the NH (8a,
9a, 10a, 13a) and NMe (8b, 12b, 13b) series exhibited acceptable
binding affinity (pKi >7.4) and functional potency (pEC50 >7.9) along
with high intrinsic activity (IA >82% of the maximum response
achieved by 5-HT in a cAMP accumulation assay) at the human re-
combinant 5-HT4 receptor. In addition, these same compounds
were highly selective (>700-fold) over the 5-HT3 receptor. The

6050
D. D. Long et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6048–6052
SO2Me
N
N
O
O
(iii)
(i)
(ii)
OH
Bn
Boc
H
N
N
H
N
N
Cl
Cl
H
Bn
OH
OH
N
14-(S)-OH
15-(R)-OH
Scheme 2. Reagents and conditions: (i) For 14: (a) (R)-epichlorohydrin, hexane; For 15: (a) (S)-epichlorohydrin, EtOH, (b) NaOH, THF, H2O, 0 °C; (ii) H2, Pd(OH)2, Boc2O,
EtOAc, 60 psi; (iii) (a) 6, DIPEA, MeOH, 80 °C, (b) TFA, DCM, (c) MsCl, DBU, DCM, 0 °C.
SO2Me
N
N
O
O
(ii)
(i)
OH
H
N
SO2Me
N
H
N
H
O
SO2Me
(iii)
N
Velusetrag (TD-5108) (15): HCl salt
16
17
Scheme 3. Reagents and conditions: (i) 50% NaOH in H2O then (S)-epichlorohydrin, 4 °C; (ii) 6 (TFA salt), EtOH, 50% NaOH in H2O, reflux; (iii) HCl, EtOH.
Table 1
5-HT4 IAd
RLM t1/2 (min)
Caco-2 Kp (1 Â 10À6
hERG inhibitione (%)
c
Compound
Series (stereochem.)
5-HT4 pKia
Selectivity versus
5-HT3
5-HT4 pEC50
b
cm/s)
Cisapride
Tegaserod
4
5
8a
8b
9a
9b
10a
10b
11a
11b
12a
12b
13a
13b
14
—
—
—
(S)
7.0
8.4
8.0
7.9
7.5
7.4
7.8
7.3
7.6
7.0
7.0
7.3
7.3
7.4
7.7
7.7
7.3
7.7
20
580
980
7400
2200
1500
3300
1800
2400
870
7.1
8.6
8.0
8.7
8.2
7.9
8.3
7.7
7.9
7.5
—
71
92
53
114
96
95
82
95
82
95
—
47
—
100
33
9
4
—
11
—
—
—
—
>90
>90
>90
>90
>90
>90
>90
>90
—
>90
>90
>90
>90
—
11
31
14
6
16
0
1
0
—
3
33
35
35
—
31
19
25
NH (rac)
NMe (rac)
NH (rac)
NMe (rac)
NH (rac)
NMe (rac)
NH (rac)
NMe (rac)
NH (rac)
NMe (rac)
NH (rac)
NMe (rac)
NMe (S)
NMe (R)
860
260
—
7.7
—
87
—
64
74
40
10
16
9
1600
710
1200
1400
110
8.0
8.1
8.0
7.6
8.3
84
107
96
97
95
>90
>90
>90
15
3300
13
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.
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
channels.
difference in pKi for a given neutral secondary binding group be-
tween the NH and NMe analogues was in general minimal ( pKi
<0.3 log) and was only significant for the urea compounds 9a,b
and 10a,b ( pKi >0.5 log); the NH 9a, 10a compounds displaying
the higher affinity value. Stability in the rat liver microsome
(RLM) assay was high (t1/2 >90 min) for all the compounds 8–
13a,b tested. The permeability (as measured by the Caco-2 assay)
was low for all the NH series compounds tested 8–13a, (Kp <6) with
the surprising exception of the carbamate analogue 12a (Kp = 35). In
contrast the permeability of the NMe series compounds 8–13b was
in general much improved (Kp >16) with the exception of primary
urea analogue 9b (Kp = 1) which was poorly permeable in both ser-
ies. We previously postulated that the H-bond donating character
of functionalized secondary binding groups of 5-HT4 receptor ago-
nists may contribute to low permeability and these results are in
general consistent.4 The NMe carbamate 12b retained the good per-
meability (Kp = 35) of its NH analogue 12a but unfortunately both
compounds demonstrated potent inhibition of the hERG potassium
D
D
ion current (40% and 74% inhibition of the channel at 3 lM, respec-
tively). The fully substituted urea 11b with no H-bond donating
character also displayed potent hERG inhibition (64%). However,
the NH sulfonamide compound 13a, its NMe analogue 13b and
the NMe amide 8b showed encouragingly weak inhibition (10%,
16% and 11%, respectively).
Due to the good overall balance of high potency, high in vitro
permeability and weak hERG inhibition observed with compound

D. D. Long et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6048–6052
6051
Figure 3. X-ray crystal structure of the hydrochloride salt of compound 15.
13b its single enantiomers 14 and 15 were synthesized and pro-
filed, Table 1, Scheme 2. Following the same trend as observed with
THRX-194556 (5) and single enantiomer indazole–tropane ana-
logues previously reported,4 the (R)-enantiomer 15 was found to
be preferable.7 (R)-Enantiomer 15 exhibited weak hERG inhibition
and had significantly higher 5-HT4 receptor affinity and functional
potency, and selectivity over the 5-HT3 receptor, relative to the (S)-
enantiomer 14. The designation of (R)-stereochemistry of the hy-
droxyl was unambiguously assigned by a crystal structure of the
hydrochloride salt of compound 15, Figure 3.
The oral pharmacokinetics (PK) in rats of the (R)-enantiomer 15
was determined and found to be improved, as reflected by
increased Cmax and AUC, relative to that of the previously identified
THRX-194556 (5) and was comparable to TD-2749 (4) albeit with a
reduced oral bioavailability, Table 2. Having achieved the goal of
discovering a 5-HT4 receptor agonist possessing a neutral second-
ary binding group with suitable potency, selectivity and oral phar-
macokinetics, the NMe sulfonamide compound 15 was selected for
further in vitro8 and in vivo9 evaluation. In parallel with these
activities a medicinal chemistry program to optimize the sulfon-
amide moiety was pursued, principally exploring alternates to
both methyl groups (NMe and SO2Me) and this will be the subject
of a future article.
was higher and compound 15 elicited a full agonist (IA = 110%) re-
sponse. These results are consistent with the full agonist properties
of THRX-194556 (5) but in contrast to the partial agonist profile of
TD-2749 (4).
Compound 15 produced a concentration-dependent contraction
of the guinea pig isolated colonic longitudinal muscle/myenteric
plexus preparation. The potency of 15 (pEC50 = 7.9) was similar to
that of 5-HT and tegaserod (2) (pEC50 = 8.0 and 8.2, respectively).
However, 15 had an intrinsic activity greater than that of tegaserod
(83% vs 65% of the 5-HT maximum, respectively). Considering the
wealth of literature demonstrating that 5-HT4 receptor activation
results in contraction of this smooth muscle preparation,10,11 and
the presence of antagonists of 5-HT1, 5-HT2 and 5-HT3 receptors
in these isolated tissue experiments, the observed activity of 15
was concluded to represent 5-HT4 receptor activation.
To characterize the in vivo activity of 15, digital sonomicrome-
try was used to monitor 5-HT4 receptor-mediated esophageal
relaxation in the anesthetized rat.12 This method provided a novel
and sensitive means to demonstrate 5-HT4 receptor agonist-medi-
ated changes in endogenous esophageal tone. Compound 15 pro-
duced a dose-dependent, 5-HT4 receptor-mediated relaxation of
the esophagus, following intravenous administration, Figure 4.
The mean ED50 values for the relaxation response mediated by
intravenous tegaserod, 15 and cisapride were 11, 25 and 142
With respect to selectivity over other 5-HT receptors, com-
pound 15 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
lg/kg, respectively. However, following intraduodenal dosing in
the rat, 15 was approximately fivefold more potent than tegaserod
10 lM. In contrast, tegaserod displays relatively high binding affin-
(data not shown).
ity (pKi >7.0) at 5-HT1D, 5-HT2A,C and 5-HT7 receptors, and has par-
ticularly 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 15 in the func-
tional cAMP accumulation assay were determined to be high
(pEC50 = 8.3; IA = 95%) using a cell line expressing the 5-HT4(c)
receptor at 10-fold physiological levels (Bmax 500–800 fmol/mg
protein).8 When a cell line expressing the 5-HT4(c) receptor at
100-fold physiological levels was used the potency (pEC50 = 9.2)
In the guinea pig colonic transit model, 15 (0.3 mg/kg sc) pro-
duced a statistically significant decrease in the colonic transit time
Compound 15
Tegaserod
Cisapride
0.25
0.20
0.15
0.10
0.05
0.00
-0.05
Table 2
a
Compound
Cmax
(l
g/mL)
AUC(0-t)
(l
g h/mL)
t1/2 (h)
Fb (%)
4
5
15
0.254
0.031
0.160
0.73
0.20
0.46
3.2
5.2
1.9
>100
20
19
0.1
1
10
100
1000 10000
Dose (µg/kg iv)
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.
Figure 4. Relaxation of rat esophagus following intravenous dosing of compound
15.
b
F = oral bioavailability.

6052
D. D. Long et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6048–6052
and 50 mg, qd).17 Velusetrag also improved stool consistency,
Vehicle
and reduced both straining and the use of laxatives. In both the
Phase 1 and Phase 2 studies velusetrag was well tolerated.
Following on from our previous efforts utilizing our multivalent
approach to drug discovery towards 5-HT4 receptor agonists we fo-
cused on identification of neutral secondary binding groups. Com-
bination of a quinolone–tropane primary binding group with a
chiral 2-propanol linker to a neutral N-methyl-methylsulfonamide
secondary binding group afforded velusetrag (TD-5108), which
was selected as a development candidate. Velusetrag is a potent
and highly selective 5-HT4 receptor agonist in vitro with robust
in vivo GI activity and an attractive oral pharmacokinetic profile.
In human subjects, velusetrag has achieved proof-of-concept in pa-
tients with chronic idiopathic constipation and shown clinical evi-
dence for potential utility in the treatment of both upper and lower
GI disorders. Velusetrag has been well tolerated in all clinical trials
to date and is currently under active development.
Compound 15 (0.003mg/kg)
Compound 15 (0.03mg/kg)
Compound 15 (0.3mg/kg)
Compound 15 (3mg/kg)
400
300
200
100
0
*
Figure 5. Guinea pig colonic transit following subcutaneous dosing of compound
15.
of carmine red dye relative to vehicle treated animals. Following
subcutaneous administration, prokinetic activity was evident
when the distance traveled by the dye was measured 60 min later
(data not shown), or when the time for excretion of the first fecal
pellet containing the marker was recorded, Figure 5. In this assay,
15 appeared to have superior potency to tegaserod, although tegas-
erod did not achieve a statistically significant increase in colonic
transit at the doses tested.
Acknowledgments
The authors would like to thank Dr. Jeff Finer from Theravance,
Inc. for his assistance in reviewing this article, Dr. Robert Chao for
work related to crystal structure determination and Shanti
Amagasu for electrophysiology work.
References and notes
Additional profiling of 15 included demonstration of good oral
bioavailability and GI motility in dogs.9,13 The effects of 15 on
1. Camilleri, M.; Kerstens, R.; Rykx, A.; Vandeplassche, L. N. Engl. J. Med. 2008, 358,
2344.
secretion of soluble amyloid precursor protein alpha (sAPPa from
HEK293 cells-stably transfected with human 5-HT4(d) receptor
and human APP695 in an in vivo model of cognition (rat Morris
water maze) were also examined.2 The results obtained support a
potential role for potent and efficacious 5-HT4 receptor agonists
in providing symptomatic and disease-modifying benefit in the
treatment of Alzheimer’s disease.
Subsequently compound 15 was nominated as a development
candidate, velusetrag (TD-5108) and advanced to human clinical
trials. Accordingly an alternate, optimized synthesis of velusetrag
was devised to support IND-enabling studies and clinical manufac-
ture, Scheme 3.14 The key chiral NMe-sulfonamide substituted
epoxide 17 was prepared in a single step by reaction of MeNHSO2Me
16 with (S)-epichlorohydrin under basic aqueous conditions. It is
believed that opening of the epoxide occurs first with subsequent
base mediated closure of the hydroxy chloro intermediate to yield
17. Reaction of this functionalized epoxide 17 with the quinolone
tropane 6 and subsequent freebasing and crystallization as the
hydrochloride salt afforded velusetrag.
In healthy human subjects, dose-related prokinetic activity,
including increases in stool production, were observed with single
doses of velusetrag up to 70 mg and repeated daily doses of up to
50 mg for 14 days.15 The pharmacokinetics of velusetrag over the
single dose-range demonstrated dose-dependent increases in sys-
temic exposure and was supportive of once daily dosing (elimina-
tion half-life of 12–14 h). These pharmacokinetic findings were
similar in patients with chronic constipation from a separate study
in which velusetrag was shown to increase gastric emptying as
well as intestinal and colonic transit in healthy volunteers, sug-
gesting utility in both upper and lower GI disorders.16 In a large
(n = 401), proof-of-concept, Phase 2 trial (ACCORD) in patients with
chronic idiopathic constipation velusetrag showed statistically and
clinically significant increases relative to placebo in both weekly
spontaneous bowel movement frequency and the weekly fre-
quency of complete SBM at all three doses tested (15 mg, 30 mg
2. Shen, F.; Smith, J. A. M.; Chang, R.; Bourdet, D. L.; Tsuruda, P. R.; Obedencio, G.
P.; Beattie, D. T. Neuropharmacol 2011, 61, 69.
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R. A. L.; Goldblum, A. A.; Humphrey, P. P.; Marquess, D. G.; Shaw, J. P.; Smith, J.
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6. McKinnell, R. M.; Armstrong, S. R.; Beattie, D. T.; Choi, S.-K.; Fatheree, P. R.;
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5330.
7. In the case of compound 15 with the NMeSO2Me secondary binding group the
(R)-OH-designation corresponds to the same relative configuration as the (S)-
OH-designation of THRX-194556 (5) with the piperazine–sulfonamide
secondary binding group.
8. Smith, J. A. M.; Beattie, D. T.; Marquess, D.; Shaw, J.-P.; Vickery, R. G.;
Humphrey, P. P. A. Naunyn Schmiedebergs Arch. Pharmacol. 2008, 378, 12.
9. 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.
10. Briejer, M. R.; Bosmans, J. P.; Van Daele, P.; Jurzak, M.; Heylen, L.; Leysen, J. E.;
Prins, N. H.; Schuurkes, J. A. Eur. J. Pharmacol. 2001, 423, 71.
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Obedencio, G.; Smith, J.; Humphrey, P. AAPS Ann. Meet. Expos. 2007, 9, 2422.
14. Complete synthesis of velusetrag is described in Marquess, D.; Fatheree, P. R.;
Turner, S. D.; Long, D. D.; Choi, S.-K.; Goldblum, A. A.; Genov, D. U.S. Patent
2008, 114, 7375.
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