Identification of (R)-1-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1H- indazol-4-yl)urea (ABT-102) as a potent TRPV1 antagonist for pain management

Article abstract of DOI:10.1021/jm701007g

Vanilloid receptor TRPV1 is a cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation by several pharmaceutical companies in an effort to identify novel agents for pain management. Here we report that replacement of substituted benzyl groups by an indan rigid moiety in a previously described N-indazole-N′-benzyl urea series led to a number of TRPV1 antagonists with significantly increased in vitro potency and enhanced drug-like properties. Extensive evaluation of pharmacological, pharmacokinetic, and toxicological properties of synthesized analogs resulted in identification of (R)-7 (ABT-102). Both the analgesic activity and drug-like properties of (R)-7 support its advancement into clinical pain trials.

Full text of DOI:10.1021/jm701007g

392
J. Med. Chem. 2008, 51, 392–395
Table 1. In Vitro Functional Potencies of Selected Indan TRPV1
Identification of (R)-1-(5-tert-Butyl-2,3-dihy-
dro-1H-inden-1-yl)-3-(1H-indazol-4-yl)urea
(ABT-102) as a Potent TRPV1 Antagonist for
Pain Management
Antagonists to Block Human TRPV1 Receptor-Mediated Ca2+ Influxa
Arthur Gomtsyan,* Erol K. Bayburt, Robert G. Schmidt,
Carol S. Surowy, Prisca Honore, Kennan C. Marsh,
Steven M. Hannick, Heath A. McDonald, Jill M. Wetter,
James P. Sullivan, Michael F. Jarvis, Connie R. Faltynek,
and Chih-Hung Lee
cmpd
R
hTRPV1 IC50 (nM)b
4
7
8
9
5-CF3
5-tert-Bu
5-Br
5-Cl
5-F
3 ( 1.6
6 ( 1
9 ( 4
10 ( 6
52 ( 21
14 ( 4
10 ( 2
7 ( 2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Global Pharmaceutical Research and DeVelopment, Neuroscience
Research, Abbott Laboratories, 100 Abbott Park Road,
Abbott Park, Illinois 60064
5-piperidino
4-piperidino
4-(4-CF3-piperidino)
4-cyclopropyl
5-cyclopropyl
4-CF3
5 ( 1
4 ( 1
ReceiVed August 13, 2007
10 ( 3
4 ( 1
40 ( 16
21 ( 2
19 ( 5
65 ( 14
5 ( 2
46 ( 5
11 ( 1
7200 ( 3500
595 ( 210
151 ( 76
4-tert-Bu
5-OMe
Abstract: Vanilloid receptor TRPV1 is a cation channel that can be
activated by a wide range of noxious stimuli, including capsaicin, acid,
and heat. Blockade of TRPV1 activation by selective antagonists is
under investigation by several pharmaceutical companies in an effort
to identify novel agents for pain management. Here we report that
replacement of substituted benzyl groups by an indan rigid moiety in
a previously described N-indazole-N′-benzyl urea series led to a number
of TRPV1 antagonists with significantly increased in vitro potency and
enhanced drug-like properties. Extensive evaluation of pharmacological,
pharmacokinetic, and toxicological properties of synthesized analogs
resulted in identification of (R)-7 (ABT-102). Both the analgesic activity
and drug-like properties of (R)-7 support its advancement into clinical
pain trials.
4-pyrrolidino
4-C(CN)Me2
4-morpholino
5-F, 4-morpholino
4-Me
5-Me
6-Me
7-Me
H
a For the assay details, see ref 11. b All values are means ( SEM of at
least three separate experiments.
distribution of 1 likely contributed to weak analgesic potency.
Alkylation at the benzylic carbon atom (e.g., compounds 2 and
3) improved these pharmacokinetic parameters, but their in vitro
potencies were 5–10-fold lower than the unsubstituted analogs.13
Therefore, the goal was to find ways of increasing TRPV1
antagonist potency of R-benzyl-substituted compounds such as
2 and 3, but at the same time retaining their improved PK profile.
Further SAR studies in which substitution at the benzylic carbon
atom was extended to form rigid bicyclic fragments ac-
complished that goal. While there are several different ways of
forming such conformationally restricted fragments, for example,
indan 4, chroman 5, and tetrahydroquinoline 6, this paper
describes SAR studies on the indan chemotype that culminated
in the identification of (R)-7 (ABT-102), a TRPV1 antagonist
possessing activity in a wide range of preclinical pain models.
The general synthetic strategy was based on using ap-
propriately substituted indanones that were converted to amines
in two steps and then reacted with indazole isocyanate to yield
the target molecules after carbamate deprotection (Scheme 1).
Utilization of an indan scaffold resulted in two important SAR
findings. First, cyclic TRPV1 antagonists were significantly
more potent than their acyclic analogs (compare compounds 2
and 3 with 4, Figure 1). Second, although para-substitution was
superior to meta-substitution in the acyclic series,10,14 both
5-(para-) and neighboring 4-(meta-) positions offered equally
good opportunities for activity improvements in the indan series.
The representative examples include indans with trifluoromethyl
(4 vs 16), tert-butyl (7 vs 17), piperidino- (11 vs 12), and cyclo-
propyl (14 vs 15) substitutions (Table 1).
The nociceptive role of vanilloid receptor TRPV1, which is
a member of the transient receptor potential ion channel family,
has been extensively discussed.1,2 Since its cloning in 1997,3
TRPV1 has generated significant interest among academic and
industrial pain researchers as a result of its unique role in pain
pathways. TRPV1 can be activated by a wide range of stimuli,
including exogenous capsaicin, endogenous arachidonic acid
metabolites, physical stimuli, such as heat, and chemical stimuli,
such as acidic media.4 In addition, activation of TRPV1 can be
potentiated by pro-nociceptive mediators such as bradykinin,
ATP, NGF, and others.5 Such promiscuity of TRPV1 regulation
makes this receptor a principle integrator of noxious stimuli
and, therefore, points to a significant role that TRPV1 may play
in pain pathways.
While both TRPV1 agonists6 and antagonists7 are being
targeted as potential analgesics, the major focus of the drug
discovery effort has been on the identification of TRPV1
antagonists. It has been well documented that TRPV1 antago-
nists can effectively reduce inflammatory hyperalgesia in animal
models.8 More recently, it was demonstrated that the analgesic
profile of TRPV1 antagonists can be significantly broaden if
the blockade of TRPV1 receptors occur both in the periphery
as well as in the central nervous system.9
Our early lead compound 110 (Figure 1) possessed good
selectivity and in vitro potency11 in blocking the activation of
TRPV1 by several ligands, but in spite of analgesic activity in
animal models after intraperitoneal administration,12 its oral
activity was modest. The short half-life and low volume of
The least favorable positions for the phenyl ring substitution
were 6 and 7, as evidenced by comparison of regioisomers
23–26. Incorporation of a nitrogen atom into the phenyl ring of
* To whom correspondence should be addressed. Tel.: 847-935-4214.
Fax: 847-937-9195. E-mail: arthur.r.gomtsyan@abbott.com.
10.1021/jm701007g CCC: $40.75
2008 American Chemical Society
Published on Web 01/10/2008

Letters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 3 393
Figure 1
Scheme 1a
Table 2. In Vitro Comparison of Indan with aza-Indans to Block
Human TRPV1 Receptor-Mediated Ca2+ Influxa
a Reagents and conditions: (a) H2NOMe·HCl, Py, 16 h, rt; (b) H2, 10%
Pd/C, MeOH-NH3; (c) 4-isocyanato-1-methoxycarbonyl-1H-indazole,
CH2Cl2, rt; (d) 5 M NaOH in MeOH, 30 min, rt.
Scheme 2a
a All values are means ( SEM of at least three separate experiments.
Table 3. SAR variations to the compound 7a
a Reagents and conditions: (a) 3-chloropropionyl chloride, AlCl3, CH2Cl2,
0 °C; (b) concd H2SO4, 90 °C, 36% for 2 steps; (c) isoamyl nitrite, concd
HCl, MeOH, 44 h, rt, used crude in the next step; (d) H2, 10% Pd/C, AcOH-
concd H2SO4, 17 h, 60 psi, rt, 50% for 2 steps; (e) see Scheme 1, steps (c)
and (d).
cmpd
R1
R2
X
hTRPV1 IC50 (nM)
7
H
H
H
F
H
H
H
H
F
O
S
6 ( 1
97 ( 36
34 ( 20
35 ( 8
30
31
32
33
N-CN
O
O
F
216 ( 65
a All values are means ( SEM of at least three separate experiments.
the indan moiety did not prove to be advantageous (Table 2).
It was previously reported that in the cinnamide series of TRPV1
antagonists the lipophilic aryl fragment tolerates replacement
of the phenyl group with pyridine.15 However, in our case, two
model aza-indan compounds 28 and 29 were much less potent
at TRPV1 receptors than the parent indan 27.
Additional SAR studies that consisted of replacements of the
urea fragment with thiourea and cyanoguanidine, as well as
attachment of fluorine atoms on the saturated indan ring, did
not yield superior compounds in terms of functional antagonist
activity at TRPV1 (Table 3).
Moving the site of attachment of urea moiety from position
1 to 2 in the indan fragment resulted in the compound 38
(Scheme 2). Friedel–Crafts acylation of the 4-tert-butylbenzene
(34) by 3-chloropropionyl chloride, followed by cyclization of
the resulting chloroketone in the presence of concd H2SO4,
provided the indanone 35. The latter was first converted to the
keto-oxime 36, which was then hydrogenated to obtain the
amine 37 by using a modified version of a previously reported
procedure.16 Acylation of 37 by indazole isocyanate followed
by deprotection gave urea 38 with TRPV1 IC50 value of 10
nM, which is comparable to regioisomeric 7.
Several potent TRPV1 antagonists shown in Table 1 were
evaluated for their pharmacokinetic profile, metabolism, brain
penetration, activity in animal pain models, and cardiovascular
side effects in anesthetized rats and dogs (data not shown). Based
on that evaluation, compound 7 showed the best combination
of favorable properties and was chosen for further studies. Due
to the presence of stereogenic center in 7, both enantiomers
were synthesized (Scheme 3). The indanone 35 was converted
to the amine 39, which was subjected to chiral resolution by

394 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 3
Letters
Scheme 3a
a Reagents and conditions: (a) see Scheme 1, (a) and (b); (b) (i) N-acetyl-
(D)-leucine, MeOH, 65 °C, 1 h, then cool to rt, filter, repeat the process
with the solid, (ii)1 N NaOH; (c) (i) N-acetyl-(L)-leucine, MeOH, 65 °C,
1 h, then cool to rt, filter, repeat the process with the solid, (ii)1 N NaOH;
(d) see Scheme 1, (c) and (d).
Table 4. Selected Pharmacokinetic Properties of (R)-7 (10 µmol/kg) in
Figure 2. (R)-7 has full efficacy against acute inflammatory thermal
hyperalgesia induced by intraplantar carrageenan in the rat. Circles
represent paw withdrawal latencies ipsilateral to the injury; squares
represent paw withdrawal latencies contralateral to the injury.
Data represent mean ( SEM [F(7,95) ) 26.61, p < 0.0001]. **p
< 0.01, as compared to vehicle-treated animals. ++p < 0.01, as
compared to carrageenan-treated paw (n ) 12 per group).
Rat, Dog, and Monkey, Administered in PEG-400a
T1/2
Vꢀ
CLp
Cmax
species
(h) iv
(L/kg), iv
(L/h·kg), iv
(µg/mL) po
F (%)
rat
dog
monkey
1.7
2.8
1.10
0.25
70
1.8b
1.9b
1.6b
1.7b
0.62b
0.59b
0.39, 0.65c
0.31
22,60c
25
a Three animals per each group, iv and oral. b Administered at 5 µmol/kg.
(R)-7 is very low (102 ng/mL at pH 1 and 57.3 ng/mL at pH
6.8), it is predicted to be well absorbed in humans based on the
value of Papp >18 × 10-6 cm/s in human Caco-2 permeability
studies. Because the oral bioavailability of poorly soluble
compounds is highly dependent on formulation, a number of
formulations were tested in an effort to improve the oral
bioavailability of (R)-7. For example, oral bioavailability of 5
µmol/kg (R)-7 in dog was increased from 22 to 60% by
replacing PEG-400 with a lipid vehicle (Table 4).
(R)-7 exhibited potent analgesic activity in a number of
animal pain models after oral administration. For example, in
the carrageenan-induced thermal hyperalgesia model, (R)-7
significantly decreased thermal hyperalgesia induced by carra-
geenan injection, as is evidenced by an increase in paw
withdrawal latency to a thermal stimulus. There was a dose-
dependent effect of (R)-7 with an ED50 of 20 µmol/kg and full
efficacy at 100 µmol/kg (Figure 2). (R)-7 was also potent in a
number of animal models of chronic pain, including inflam-
matory, osteoarthritis, bone cancer, and postoperative pain.20
The ability of (R)-7 to penetrate CNS (brain/plasma ratio 0.32)
could be one of the reasons for its broad-spectrum analgesic
profile compared to other previously described TRPV1 receptor
antagonists.9
c Oleic acid/cremophor/PEG-400 (80:10:10).
N-acetyl-L- and D-leucine by analogy to a similar reported
procedure.17 The absolute configuration of the enantiomerically
pure amine (S)-39 was established by X-ray analysis of its
N-acetyl-L-leucine salt. Elaboration of the chiral amines to the
target compounds (R)-7 and (S)-7 proceeded as shown in
Scheme 1.18 (R)-7 displayed 30-fold higher potency in blocking
activation of TRPV1 by capsaicin than its enantiomeric coun-
terpart (S)-7 (IC50 4 nM vs 123 nM). Because of the polymodal
nature of the TRPV1 receptor and its ability to integrate
numerous signals present during chronic pain, it is likely that
an ideal antagonist would also be one that shows good potency
across multiple modes of TRPV1 activation.2 (R)-7 blocked the
activation of TRPV1 by other stimuli such as N-arachidonoyl-
dopamine (NADA) and pH 5.5, with IC50 values of 3 nM and
0.7 nM, respectively. Full blockage of heat activation (50 °C)
of the receptor was observed after application of (R)-7 at the
concentration of 100 nM.19 In addition to the in vitro potency
difference, chiral discrimination was also observed in PK
properties such as half-lives, volumes of distribution, and Cmax
(see Supporting Information). (R)-7 was highly selective and
showed little or no effect at 10 µM in a study using a panel of
ion channels, other receptors, and transporters (CEREP, Poitiers,
France).19
The in vitro rate of metabolism of (R)-7 in rat, dog, and
human liver microsomes was low and similar across species:
in vitro intrinsic clearance values Clint in liver microsomes were
0.34 mL/min/mg (rat), 0.12 mL/min/mg (dog), and 0.10 mL/
Pharmacokinetic evaluation of (R)-7 was performed in rats,
dogs, and monkeys (Table 4). Although aqueous solubility of
Scheme 4a
a Reagents and conditions: (a) MeOH, AcCl, reflux, 2.5 h, 100%; (b) MeI, NaH, THF, 0 °C-rt, 14 h, 66%; (c) LiAlH4, THF, rt, 2 h, 98%; (d) t-BuMe2SiCl,
imidazole, DMF, rt, 2 h, 97%; (e) trimethylsilylacetylene, Pd(PPh3)2Cl2,CuI, MeCN-Et3N, reflux, 14 h, 66%; (f) CO, 500 psi, [Rh(COD)Cl]2,
Ph3P,THF-H2O-Et3N, 160 °C, 71%; (g) see Scheme 1, steps a, b; (h) see Scheme 1, steps c, d; (i) TBAF (1 M in THF), THF, 14 h, rt, 70%; (j) chiral
separation with Chiralcel OD-column, hexane-MeOH-EtOH, 75:12.5:12.5.

Letters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 3 395
phthalazine, quinoxaline, and cinnoline moieties. J. Med. Chem. 2005,
48, 744–752.
min/mg (human). The major metabolite was identified as the
alcohol 47. To characterize pharmacological properties of 47
and to assess its possible contribution to in vivo effects of (R)-
7, the synthesis of the metabolite was carried out in 10 steps as
shown in Scheme 4. The key step was preparation of the
indanone 44 in 71% yield from the alkynyl intermediate 43 by
Rh-catalyzed cyclocarbonylation reaction. The alcohol 47 was
about 30-fold weaker (IC50 127 nM) than (R)-7 at TRPV1 and
was significantly less active in animal pain models as can be
illustrated by comparison of its ED50 value of >100 µmol/kg
versus 20 µmol/kg for (R)-7 in the carrageenan-induced thermal
hyperalgesia pain model.
Recent data indicate that TRPV1 antagonists produce about
1 °C increase in core body temperature at analgesic doses.21,22
Consistent with this data, systemically administered (R)-7
produced a similar increase in core body temperature. However,
this hyperthermic effect is transient and ameliorates following
repeated dosing.20
In summary, replacement of the benzyl lipophilic portion in
the urea series of TRPV1 antagonists with an indan moiety led
to the identification of (R)-7. Despite low aqueous solubility,
this compound exhibited good oral bioavailability when suitable
lipid formulations were employed. Its broad-spectrum analgesic
profile across preclinical pain models makes (R)-7 a suitable
candidate for clinical studies. Full pharmacological profile of
the compound will be described elsewhere.19,20
(11) El Kouhen, R.; Surowy, C. S.; Bianchi, B. R.; Neelands, T. R.;
Mcdonald, H. A.; Niforatos, W.; Gomtsyan, A.; Lee, C.-H.; Honore,
P.; Sullivan, J. P.; Jarvis, M. F.; Faltynek, C. R. A-425619 [1-Iso-
quinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea], a novel and selective
transient receptor potential type V1 receptor antagonist, blocks channel
activation by vanilloids, heat, and acid. J. Pharmacol. Exp. Ther. 2005,
314, 400–409.
(12) Honore, P.; Wismer, C. T.; Mikusa, J.; Zhu, C. Z.; Zhong, C.; Gauvin,
D. M.; Gomtsyan, A.; El Kouhen, R.; Lee, C.-H.; Marsh, K. C.;
Sullivan, J. P.; Faltynek, C. R.; Jarvis, M. F. A-425619 [1-isoquinolin-
5-yl-3-(4-trifluoromethyl-benzyl)-urea], a novel and selective transient
receptor potential type V1 receptor antagonist, relieves pathophysi-
ological pain associated with inflammation and tissue injury in rats.
J. Pharmacol. Exp. Ther. 2005, 314, 410–421.
(13) Gomtsyan, A.; Bayburt, E. K.; Keddy, R.; Turner, S. C.; Jinkerson,
T. K.; Didomenico, S.; Perner, R. J.; Koenig, J. R.; Koenig; McDonald,
H. A.; Surowy, C. S.; Honore, P.; Mikusa, J.; Marsh, K. C.; Wetter,
J. M.; Faltynek, C. R.; Lee, C.-H. R-Methylation at benzylic fragment
of N-aryl-N′-benzyl ureas provide TRPV1 antagonists with better
pharmacokinetic properties and higher efficacy in inflammatory pain
model. Bioorg. Med. Chem. Lett. 2007, 17, 3894–3899.
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T. K.; Brown, B. S.; Keddy, R. G.; McDonald, H. A.; Honore, P.;
Wismer, C. T.; Marsh, K. C.; Wetter, J. M.; Polakowski, J. S.; Segreti,
J. A.; Jarvis, M. F.; Faltynek, C. R.; Lee, C.-H. Structure-activity
studies of a novel series of 5,6-fused heteroaromatic ureas as TRPV1
antagonists. Bioorg. Med. Chem. 2006, 14, 4740–4749.
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Gavva, N.; Han, N.; Kelly, M. G.; Kincaid, J.; Klionsky, L.; Liu, Q.;
Ognyanov, V. I.; Tamir, R.; Wang, X.; Zhu, J.; Norman, M. H.;
Treanor, J. J. S. Discovery of potent, orally available vanilloid
receptor-1 antagonists. Structure-activity relationship of N-aryl cin-
namides. J. Med. Chem. 2005, 48, 71–90.
(16) Cannon, J. G.; Perez, J. A.; Bhatnagar, R. K.; Long, J. P.; Sharabi,
F. M. Conformationally restricted congeners of dopamine derived from
2-aminoindan. J. Med. Chem. 1982, 25, 1442–1446.
(17) Smith, H. E.; Willis, T. C. Optical rotatory dispersion and circular
dichroism of the N-salicylidene derivatives of R- and ꢀ-phenylalkyl-
aminessThe absolute configurations of some phenylnorbornanes.
Tetrahedron 1970, 26, 107–118.
Acknowledgment. We thank Mr. R. Henry for X-ray analysis
of (S)-39.
Supporting Information Available: Complete experimental and
characterization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
(18) For a large-scale asymmetric synthesis of ABT-102, see Lukin, K.;
Chambournier, G.; Kotecki, B.; Venkatramani, C. J.; Leanna, M. R.
Development of a large-scale asymmetric synthesis of vanilloid
receptor (TRPV1) antagonist ABT-102. Org. Proc. Res. DeV. 2007,
11, 578–584.
(19) Surowy C. S.; Neelands T. R.; Bianchi B. R.; McGaraughty S.; Chu
K.; McDonald H. A.; El-Kouhen R.; Han P.; Vos M.; Niforatos W.;
Lee C.-H.; Gomtsyan A.; Honore P.; Sullivan J. P.; Jarvis M. F.;
Faltynek C. R. ABT-102 (1-((R)-5-tert-butyl-indan-1-yl)-3-(1H-inda-
zol-4-yl)-urea) blocks polymodal activation of TRPV1 receptors in
vitro and heat-evoked firing of spinal dorsal horn neurons in vivo.
Submitted for publication.
(20) Honore P.; Chandran, P.; Hernandez, G.; Gauvin, D. M.; Mikusa, J. P.;
Zhong, C.; Ghilardi, J. R.; Sevcik, M. A.; Fryer, R. M.; Segreti, J. A.;
Banfor, P. N.; Widomski, D. L.; Reinhart, G.; Marsh, K.; Neelands,
T.; Niforatos, W.; McDonald H.; Bayburt, E. K.; Daanen, J. F.;
Gomtsyan, A.; Lee, C.-H.; Surowy, C.; Mantyh, P. W.; Sullivan, J. P.;
Jarvis, M. F.; Faltynek, C. R. Repeated dosing of ABT-102, a potent
and selective TRPV1 antagonist, enhances TRPV1-mediated analgesic
activity in rodents, but attenuates antagonist-induced hyperthermia.
Submitted for publication.
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JM701007G