Stereospecific high-affinity TRPV1 antagonists: Chiral N-(2-benzyl-3- pivaloyloxypropyl) 2-[4-(methylsulfonylamino)phenyl]propionamide analogues

Article abstract of DOI:10.1021/jm701049p

Previously, we reported the thiourea antagonists 2a and 2b as potent and high affinity TRPV1 antagonists. For further optimization of the lead compounds, a series of their amide and α-substituted amide surrogates were investigated and novel chiral N-(2-be

Full text of DOI:10.1021/jm701049p

J. Med. Chem. 2008, 51, 57–67
57
Stereospecific High-affinity TRPV1 Antagonists: Chiral N-(2-Benzyl-3-pivaloyloxypropyl)
2-[4-(methylsulfonylamino)phenyl]propionamide Analogues
HyungChul Ryu,† Mi-Kyoung Jin,† Su Yeon Kim,† Hyun-Kyung Choi,† Sang-Uk Kang,† Dong Wook Kang,† Jeewoo Lee,*,†
Larry V. Pearce,‡ Vladimir A. Pavlyukovets,‡ Matthew A. Morgan,‡ Richard Tran,‡ Attila Toth,‡ Daniel J. Lundberg,‡ and
Peter M. Blumberg‡
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National UniVersity, Shinlim-Dong,
Kwanak-Ku, Seoul 151-742, Korea, and Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute,
National Institutes of Health, Bethesda, Maryland 20892
ReceiVed August 23, 2007
Previously, we reported the thiourea antagonists 2a and 2b as potent and high affinity TRPV1 antagonists.
For further optimization of the lead compounds, a series of their amide and R-substituted amide surrogates
were investigated and novel chiral N-(2-benzyl-3-pivaloyloxypropyl) 2-[4-(methylsulfonylamino)phenyl]-
propionamide analogues were characterized as potent and stereospecific rTRPV1 antagonists. In particular,
compounds 72 and73 displayed high binding affinities, with Ki values of 4.12 and 1.83 nM and potent
antagonism with Ki values of 0.58 and 5.2 nM, respectively, in rTRPV1/CHO cells. These values are
comparable or more potent than those of 5-iodoRTX under the same assay conditions. A distinctive binding
model that includes two hydrophobic pockets is proposed for this series of compounds based on docking
studies of 57 and 72 with a homology model of the TM3/4 region of TRPV1.
Introduction
for the inhibition of 45Ca2+ uptake in response to capsaicin,
albeit with a low level of residual agonism.
The TRPV1 (vanilloid receptor 1 or VR1) is a member of
the transient receptor potential (TRP) superfamily.1 The receptor
is activated by protons, heat, endogenous substances, such as
anandamide and lipoxygenase products, and by natural ligands
such as capsaicin (CAP) and resiniferatoxin (RTX).2,3 Because
TRPV1 functions as a nonselective cation channel with high
Ca2+ permeability, its activation by these agents leads to an
increase in intracellular Ca2+ that results in excitation of primary
sensory neurons and ultimately in the central perception of pain.4
The involvement of this receptor in both pathological and
physiological conditions suggests that the blocking of this
receptor activation, by desensitization or antagonism, would
have considerable therapeutic utility.5,6 TRPV1 antagonists have
attracted much attention as promising drug candidates to inhibit
the transmission of nociceptive signals from the periphery to
the CNS and to block other pathological states associated with
this receptor. The therapeutic advantage of TRPV1 antagonism
over agonism is that it lacks the initial excitatory effect preceding
the desensitization, which represents a limiting toxicity for the
systemic application of the agonists.7 Since the discovery of
capsazepine as the first TRPV1 antagonist,8 multiple classes of
antagonists have been described.9,10
We have previously reported that isosteric replacement of
the phenolic hydroxyl group in potent TRPV1 agonists, for
example, 1 (Ki ) 6.35 nM, EC50 ) 2.83 nM in rTRPV1/CHO),
with the alkylsulfonamido group provided a series of compounds
that were effective antagonists to the action of capsaicin on rat
TRPV1 heterologously expressed in Chinese hamster ovary
(CHO) cells.11 Notably, N-[2-(4-t-butylbenzyl)-3-pivaloylox-
ypropyl]-N′-[3-fluoro-4-(methylsulfonyl amino)benzyl]thiourea
(2) showed high affinity with a Ki ) 22.6 nM for the inhibition
of [3H]RTX binding and potent antagonism with a Ki ) 52 nM
As a continuation of our effort to optimize the 4-methylsul-
fonamide TRPV1 antagonists, we explored the amide surrogates
of the parent thiourea antagonists (Figure 1). Their receptor
activities were moderately reduced. Next, we undertook an
extensive SAR investigation of a series of R-substituted
analogues of amide antagonists and found that a series of
R-methyl amide analogues showed very promising activities.
In particular, a diastereomeric mixture (10) of the R-methyl
amide analogues of 3 displayed high binding affinity and potent
antagonism. This finding prompted us to synthesize the optically
pure isomers of the R-methyl amide analogues and to evaluate
their receptor activities. Here, we demonstrate that the thiourea
antagonist is optimized to an R-methyl amide antagonist for
receptor activity and that the optical isomers of R-methyl
antagonist interact with the receptor and antagonize the effect
of capsaicin in a stereospecific manner with high affinities and
potent antagonism.
Chemistry. The racemic or diastereomeric R-methyl (9-16),
dimethyl (20-22), and cyclopropyl amide (26-28) analogues
were prepared by the coupling of the corresponding 2-substituted
arylacetic acids12 and amines,11 respectively, as shown in
Scheme 1.
The syntheses of four different R-methyl amide enantiomers
are summarized in Schemes 2-4. For the synthesis of the chiral
A-region, we employed a chemical resolution from racemic
acids using L-phenylalanol. For a large scale synthesis of acids
6 and 7, we developed an efficient method, as described in
Scheme 2.
Ethyl 2-(4-nitrophenyl)propionates (31, 32) were prepared
from the corresponding 2-halonitrobenzenes (29, 30), re-
spectively, by the reaction of Makosza’s vicarious nucleo-
philic substitution.13 The 4-nitro groups of 31 and 32 were
converted to the corresponding 4-methylsulfonylamino groups
and then their esters were hydrolyzed to afford the racemic
acids, 6 and 7, respectively. These racemates were chemically
* To whom correspondence should be addressed. Phone: 82-2-880-7846.
Fax: 82-2-888-0649. E-mail: jeewoo@snu.ac.kr.
†
Seoul National University.
National Cancer Institute, National Institutes of Health.
‡
10.1021/jm701049p CCC: $40.75
2008 American Chemical Society
Published on Web 12/12/2007

58 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 1
Ryu et al.
Figure 1
Scheme 1. Synthesis of Racemic and Diastereomeric Analoguesa
a Reagents and conditions: (a) R-NH2, EDC, CH2Cl2.
separated utilizing L-phenylalanol as a resolving agent via
the diastereomeric mixtures 37 and 38 to provide the optically
pure enantiomers, 39R/39S and 40R/40S, respectively. The
absolute stereochemistry of each enantiomer was determined
based on the spectral comparison of its Evan’s oxazolidinone
derivative with that prepared from independent synthesis by
a different route. The synthesis of the chiral C-region was
accomplished by Seebach’s diastereoselective alkylation of
ꢀ-alkoxide enolate as a key reaction.14 Antiselective alky-
lations of dibenzyl L-malate (41) with benzyl or 4-t-
butylbenzyl bromides afforded 3R-benzyl-2S-hydroxysucci-
nates (42, 43), respectively, which were transformed into the
diverging intermediates (46, 47) for the synthesis of chiral
3-pivaloyloxy-2-benzylpropyl azides (S-isomers: 54/55, R-
isomers: 67/68). A coupling reaction between the chiral
A-region (39R/39S, 40R/40S) and C-region (54/55, 67/68)
provided the final R-methyl amide ligands (56-60, 69-73),
respectively.
Results and Discussion
The functional potencies of the synthesized TRPV1 ligands
as agonists and antagonists and their receptor binding affinities
were assessed in vitro by assay of 45Ca2+ uptake and by
competitive binding with [3H]RTX, respectively, in Chinese
hamster ovary cells heterologously expressing rat TRPV1 (CHO/
VR1 cells), as previously described.15 The results are sum-
marized in Tables 1 and 2.
To optimize the receptor activity of the parent 4-methylsul-
fonamide TRPV1 antagonist (2) and avoid the potential toxicity
related to the thiourea group, we explored the amide surrogates
(3, 4) of the B-region of compounds 2a and 2b. We found that
their receptor activities were moderately reduced. The binding

Stereospecific High-Affinity TRPV1 Antagonists
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 1 59
Scheme 2. Synthesis of Chiral A-Regiona
a Reagents and conditions: (a) ClCH(Me)CO2Et, t-BuOK, DMF; (b) H2, Pd-C, MeOH for R ) F; Fe, AcOH for R ) Cl; (c) MsCl, pyridine; (d) LiOH,
H2O-THF; (e) L-phenylalanol, EDC, CH2Cl2; (f) 3 N H2SO4.
Scheme 3. Synthesis of Target Compounds with (S)-C2 Chiralitya
a Reagents and conditions: (a) LHMDS, ArCH2Br, HMPA, THF; (b) LiAlH4, THF; (c) pTsOH, acetone; (d) PPh3, DPPA, DEAD, THF; (e) H5IO6, ether;
(f) NaBH4, MeOH; (g) Me3CCOCl, pyridine; (h) (i) Pd-C, MeOH; (ii) 39R/S or 40R/S, EDC, CH2Cl2.
affinities of 3 and 4 showed 3-fold reduced potencies compared
to 2a and 2b, respectively. Their antagonism was also much
reduced, but the weak efficacy as an agonist remained similar.
As the next step, we investigated the SAR of an extensive series
of R-substituted analogues of the amide antagonists and found that
a series of R-methyl amide analogues (9-12, 13-16) showed very
potent activities. In particular, a diastereomeric mixture (10) of the
R-methyl amide analogue of 3 displayed high binding affinity with
a Ki ) 13.6 nM and potent antagonism with a Ki ) 3.24 nM,
showing much greater potency than the corresponding amide (3)
and thiourea (2a) surrogates. The other R-substituted analogues
such as the dimethyl (20-22) and cyclopropyl amides (26-28),
in contrast, showed dramatic loss in receptor activity compared to
the corresponding R-methyl amide (13, 14, 16). These results
indicated that the R-methyl in the B-region might constitute an
additional pharmacophoric group for the receptor interaction,
providing hydrophobic contacts and complementing the previously
identified pharmacophores.
To follow up on the potent receptor binding and antagonism
of capsaicin by the diastereomeric mixture of 10, we next sought
to prepare the optically pure isomers of the R-methyl amide
analogues and to evaluate their receptor activities. For synthetic
convenience and confirmation of the SAR pattern, we initially
investigated the benzyl derivatives (R2 ) H, 56, 57, 69, 70).
Their receptor potencies were stereospecific and compound 57
(S,S) showed the strongest binding affinity with a Ki ) 16.5
nM. The analysis indicated that whereas the stereocenter at the
R-position was crucial for determining the potencies in binding
affinity and antagonism, the chirality of the C-region had little
effect. Similarly, the analysis of the enantiomers of 2 and 3
revealed that their receptor potencies were very close (unpub-
lished results).

60 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 1
Ryu et al.
Scheme 4. Synthesis of Target Compounds with (R)-C2 Chiralitya
a Reagents and conditions: (a) Me3CCOCl, pyridine; (b) H5IO6, ether; (c) NaBH4, MeOH; (d) PPh3, DPPA, DEAD, THF; (e) (i) Pd-C, MeOH; (ii) 39R/S
or 40R/S, EDC, CH2Cl2.
Table 1. rTRPV1 Activities of Racemic and Diastereomeric Compounds
Kia (nM) binding
b,e
X, Y
R1
R2
affinity
EC50 (nM) agonism
Kic (nM) antagonism
CPZd
5-I-RTXd
2a
3
9
10
11
12
2b
4
13
14
15
16
20
21
22
26
1300 ((150)
0.61 ((0.08)
22.6 ((2.7)
74 ((13)
NE
520 ((12)
12.2 ((4.0)
52 ((17)
NE
WEb
WEb
NE
H, H
F
H
F
Cl
OMe
4-t-Bu
4-t-Bu
4-t-Bu
4-t-Bu
4-t-Bu
440 ((190)c
52 ((11)
H, CH3
H, CH3
H, CH3
H, CH3
55 ((1.0)
13.6 ((2.4)
3.6 ((1.2)
24.0 ((4.9)
54 ((28)
157 ((37)
119 ((15)
33.1 ((8.7)
11.3 ((3.1)
71 ((19)
370 ((100)
280 ((120)
153 ((50)
396 ((66)
1580 ((290)
239 ((48)
WEb
WEb
WEb
NE
3.24 ((0.83)c
12.3 ((4.7)c
NE
7.8 ((3.0)
151 ((36)b
38 ((5.8)
10.8 ((3.6)
36 ((17)
H, H
F
H
F
Cl
OMe
H
F
OCH3
H
F
3,4-Me2
3,4-Me2
3,4-Me2
3,4-Me2
3,4-Me2
3,4-Me2
3,4-Me2
3,4-Me2
3,4-Me2
3,4-Me2
3,4-Me2
WEb
NE
H, CH3
H, CH3
H, CH3
H, CH3
CH3, CH3
CH3, CH3
CH3, CH3
(CH2)2
NE
WEb
WEb
NE
13.6 ((4.4)c
104 ((39)
65 ((16)
NE
NE
NE
NE
133 ((40)
197 ((81)
567 ((84)
118 ((32)
27
28
(CH2)2
(CH2)2
OCH3
NE
a Ki values represent mean ( SEM from 3 or more experiments. b Only fractional calcium uptake compared to 300 nM capsaicin (2a, 5%; 3, 7%; 10, 8%;
12, 40%; 15, 16%; 16, 10%). Values from 1 to 5 experiments. c Only fractional antagonism to 150 nM capsaicin (3, 56%; 4, 71%; 10, 95%; 11, 61%; 16,
63%). d CPZ: capsazepine; 5-I-RTX: 5-iodoresiniferatoxin. e NE: not effective; WE: weakly effective at 30 µM. Results from 1–5 experiments.
The receptor stereospecificity of this template was confirmed
with a series of 4-t-butylbenzyl analogues (R2 ) 4-t-Bu) 58-60
and 71-73. The S-configuration of 2-phenylpropionate (corre-
sponding to C1 in Table 2) was critical for high receptor potency.
For example, compounds 72 (S,R) and 59 (S,S) were 13- and
10-fold more potent in binding affinity and 52- and 13-fold more
potent in antagonism compared to compounds 71 (R,R) and 58
(R,S), respectively. On the other hand, the stereochemistry of
the C-region (corresponding to C2 in Table 2) modestly favored
the R-configuration for receptor potency; the difference of
potency was small for binding affinity (1.5-fold in 72(S,R)/
59(S,S); 1.2-fold in 71(R,R)/58(R,S)) but larger for antagonism
(19-fold in 72/59; 5-fold in 71/58). The stereoselectivity of the
3-chloro derivatives (60, 73) followed that of the corresponding
3-fluoro derivatives. Taken together, the order of receptor
potencies in this series can be described as C1,C2: S,R (70, 72)
> S,S (57, 59) >> R,R (69, 71) > R,S (56, 58); the binding
affinities of 57 and 70 represent the only exception, where S,S
(57) binds with 2-fold stronger affinity than does S,R (70).
The optimization of this series led to the two optimized
TRPV1 antagonists, 72 and 73, with an S,R chirality and high
receptor potencies. Under our assay conditions, their functional
activities were more potent than that of 5-iodoRTX, one of most
potent antagonists so far. Compound 72 with a 3-fluoro

Stereospecific High-Affinity TRPV1 Antagonists
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 1 61
Table 2. rTRPV1 Activities of Chiral Compounds
b,c
R1
R2
chirality (C1,C2)
Kia (nM) binding affinity
EC50 (nM) agonism
Ki (nM) antagonism
56
57
69
70
58
59
60
71
72
73
F
F
F
F
F
F
Cl
F
F
H
H
H
H
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
R,S
S,S
R,R
S,R
R,S
S,S
S,S
R,R
S,R
S,R
370 ((120)
16.5 ((2.4)
298 ((58)
43 ((13)
NE
NE
NE
NE
WEb
NE
NE
NE
NE
NE
205 ((42)
10.0 ((2.5)
98 ((18)
8.56 ((0.94)
142 ((35)
10.9 ((4.8)
12.1 ((3.9)
30.3 ((8.9)
0.58 ((0.16)
5.2 ((1.6)
64 ((9.0)
6.26 ((1.8)
3.29 ((0.67)
53.0 ((6.9)
4.12 ((0.54)
1.83 ((0.5)
Cl
a Ki values represent mean ( SEM from 3 or more experiments. b Only fractional calcium uptake compared to 300 nM capsaicin (58, 9%). Values from
1 to 5 experiments. c NE: not effective; WE: weakly effective at 30 µM. Results from 1–5 experiments.
substitution showed high binding affinity with a Ki ) 4.12 nM
and potent antagonism with a Ki ) 0.58 nM; the antagonism
was thus about 900-fold and 21-fold more potent than cap-
sazepine and 5-iodoRTX, respectively. Compound 73 with a
3-chloro substitution exhibited better binding affinity, with a
Ki ) 1.83 nM, and less potent antagonism, with a Ki ) 5.2
nM, compared to 72. The antagonism of 73 was approximately
99-fold and 2-fold more potent than capsazepine and 5-io-
doRTX, respectively.
hydrophilic surface. The calculations indicated that, in 72, the
4-t-butylbenzyl group represents the area of highest lipophilicity
(brown) and the sulfonylaminobenzyl segment represents the
area of highest hydrophilicity (blue), as shown in Figure 2a. In
the receptor, the hydrophobic binding pocket is surrounded by
Trp549, Met552, and Leu553, and the hydrophilic pocket is
formed by Ser510, Tyr511, and Ser512. On the basis of this
mapping, the docking study was conducted such that the
nonpolar part of the ligand was fitted to the hydrophobic region
of the pocket and the polar subunit was bound to the hydrophilic
region. The resultant binding model is displayed as surface-
ball and stick and ribbon-stick pictures in Figure 2b,c, respec-
tively. In the proposed model, the oxygen atom of the
sulfonamide (A-region) acts as a hydrogen bond acceptor for
the phenolic hydroxyl group of Tyr511 (2.1 Å) and the 3-fluoro
atom engages in a hydrogen bond to the amide proton of Gly563
(2.0 Å). The N-H of the amide group (B-region) makes a
hydrogen bond to the side chain of Gln561 (1.9 Å), and the
carbonyl of the ester group (C2-region) forms a hydrogen bond
with Tyr565 (1.7 Å). The hydrophobic 4-t-butylbenzyl group
(C1-region) closely contacts Phe517, Trp549, Leu553, and
Arg557 in the hydrophobic pocket designated as hole A. Of
particular note, the R-methyl next to the amide group closely
contacts the hydrophobic side chains of Tyr511, Glu513,
Arg557, and Gln560 in hole B. The hydrophobic interactions
between the methyl group and these amino acids may contribute
to the observed high binding affinity. This finding is more like
the model of Jordt and Julius in which Tyr511 interacts with
the vanillyl-moiety (A-region) and the hydrophobic tail protrudes
into the membrane.
Compound 57 contains an unsubstituted phenyl and an
S-configuration at C2 in the C-region compared to compound
72. Interestingly, the binding affinity of 57 was 2-fold stronger
than that of 70, which has the R-configuration at C2 and, thus,
shows somewhat different SAR from that of the series of
t-butylbenzyl derivatives. We, therefore, examined the docking
of compound 57; the resulting model is shown in Figure 2d.
Because only one t-butyl group in 3-pivaloyloxypropyl is present
in the compound, this group rather than the benzyl group would
bind preferentially to hole A to maintain the hydrophobic
interaction critical for high affinity. That results in the binding
affinity of the S-isomer at C2 (compound 57) being better than
that of the R-isomer (compound 70) in the benzyl series. The
interactions in the A- and B-regions of compound 57 were
similar to those found for compound 72.
Molecular Modeling. Recently, hypothetical models for the
vanilloid binding site of TRPV1 and for its molecular deter-
minants were proposed based on species differences in TRPV1
sequence, site-directed mutagenesis, homology modeling of the
transmembrane domain of TRPV1, and docking studies of
capsaicin or RTX bound to the putative binding site.16–18 In
the model of Jordt and Julius, an aromatic residue, Tyr511, on
the intracellular S2/S3 loop was predicted to interact with the
vanillyl-moiety of capsaicin. Additional polar residues, such as
Ser512 or Arg491, could interact with capsaicin via hydrogen
bonds, whereas lipophilic residues in TM3 might contribute to
hydrophobic interactions with the aliphatic moiety of capsaicin
within the plane of the membrane.16 In the model of Gavva
and co-workers, Tyr511, Met547, and Thr550 were suggested
to be present in the binding pocket, because all three residues
are important molecular determinants for vanilloid sensitivity.
This model proposed the interactions of the vanillyl moiety with
Thr550 and the “tail end” hydrophobic group of capsaicin or
RTX interacting with Tyr511.17 In the model of Middleton and
co-workers, Met547 and Tyr555 interact with the vanillyl moiety
and Tyr511 contacts the orthophenyl group of RTX. That model
also shows the additional interactions of the C3-carbonyl and
the C2-methyl of RTX with Asn551 and Leu515, respectively.18
The most distinctive difference among the three models is that
whereas Tyr 511 interacts with the vanillyl group (A-region)
in the model of Jordt and Julius, it contacts the hydrophobic
ends of RTX or capsaicin (C-region) in the models of Gavva
or Middleton and co-workers.
To investigate the binding mode of a series of the R-methyl
TRPV1 antagonists, the potent antagonist 72 (Ki ) 4.12 nM)
was docked into the transmembrane helices TM3 and TM4 of
human TRPV1, which was constructed through homology
modeling by Gavva and colleagues.17 Two alternative binding
modes are possible in the molecular docking simulation.
However, the molecular surface mapping of 72 and of the
receptor is able to distinguish their regions of hydrophobic and

62 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 1
Ryu et al.
Figure 2. (a) Surface maps color-coded by lipophilic potential (LP) of antagonist 72 and TM3/4 region of human TRPV1. The color for LP ranges
from brown (highest lipophilic area of the molecule) to blue (highest hydrophilic area). (b) Proposed models of 72 bound to TRPV1 binding site.
(c) and (d) Molecular interactions of 72 and 57 with the TRPV1 binding site, respectively.
The volumes of holes A and B were calculated using the
castP program based on the pocket algorithm of the alpha shape
theory to calculate quantitative fitting. The analysis revealed
that the holes A (147 Å3) and B (19 Å3) are suitable to
accommodate a 4-t-butylphenyl group (138 Å3) or a pivaloy-
loxymethyl group (111 Å3) and an R-methyl group (19 Å3),
respectively. For compound 72, hole A was better fitted by the
4-t-butylphenyl group than by the pivaloyloxymethyl group
because of its larger size. However, the relative preference for
t-butylphenyl would be modest because of the small volume
difference between the two groups. The result reflects the small
differences in binding affinities between stereoisomers of C2;
for example, 72 (S,R: Ki ) 4.12 nM) compared to 59 (S,S: Ki
) 6.26 nM) and 71 (R,R: Ki ) 53 nM) compared to 58 (R,S: Ki
) 64 nM). On the other hand, for compound 57, hole A is better
fit by the pivaloyloxymethyl group rather than by the smaller
phenyl group (68 Å3), resulting in a reverse chiral preference
at C2. Hole B is almost perfect for the volume of the methyl
group. Therefore, unsubstitution or the substitution of other alkyl
groups led to a dramatic loss in binding affinities and antagonism
in our SAR investigation. These docking analyses thus propose
a plausible binding mode for this series in which the R-methyl
group of the antagonists occupies hole B with a preferred
S-configuration and then the relevant group, t-butylphenyl or
pivaloyloxymethyl, fits hole A for the second crucial hydro-
phobic interaction.
Conclusion
In conclusion, we have described the optimization of the lead
thiourea 2 to afford a novel series of chiral N-(2-benzyl-3-
pivaloyloxypropyl) 2-[4-(methylsulfonylamino)phenyl] propi-
onamide analogues as rTRPV1 antagonists. The two R-methyl
amide antagonists, 72 and 73, with an S,R-stereochemistry,
displayed high binding affinity and potent antagonism and were
more potent antagonists than 5-iodoRTX under the same assay
conditions. A docking study of 57 and 72 using a homology
model of the TM3/4 region of TRPV1 demonstrated two
stereospecific hydrophobic interactions, of the R-methyl (hole
B) and 4-t-butylphenyl (or pivaloyloxymethyl) groups (hole A),
and hydrophilic interactions of the 4-(methylsulfonylamino)-3-

Stereospecific High-Affinity TRPV1 Antagonists
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 1 63
3.28 (m, 1 H, CH2NH), 2.95–3.1 (m, 4 H, SO2CH3 and CH2NH),
2.4–2.6 (m, 2 H, CH2Ar), 2.15–2.3 (m, 6 H, 2 × CH3), 2.05 (m, 1
H, CH), 1.58 (m, 2 H, CH2CCH2), 1.17 (s, 9 H, COC(CH3)3), 1.00
(m, 2 H, CH2CCH2); IR (KBr) 2972, 1721, 1652, 1584, 1511, 1336,
1285, 1159 cm-1; MS (FAB) m/z 533 (MH+); Anal. (C28-
H37FN2O5S) C, H, N, S.
fluorophenyl group (A-region) and the amide (B-region),
consistent with the SAR relations for receptor binding and for
antagonism.
Experimental Section
N-[2-(3,4-Dimethylbenzyl)-3-pivaloyloxypropyl]-1-[3-methoxy-
4-(methylsulfonylamino)phenyl]cyclopropanecarboxamide (28).
Yield 82%, white solid, mp ) 66–68 °C; 1H NMR (CDCl3) δ 7.50
(dd, 1 H, J ) 8.3, 1.3 Hz, Ar), 6.75–7.05 (m, 6 H, Ar and NHSO2),
5.65 (bt, 1 H, NH), 3.94 (m, 1 H, CH2OCO), 3.90 (s, 3 H, OCH3),
3.76 (m, 1 H, CH2OCO), 3.29 (m, 1 H, CH2NH), 2.9–3.1 (m, 4 H,
SO2CH3 and CH2NH), 2.4–2.6 (m, 2 H, CH2Ar), 2.15–2.3 (m, 6
H, 2 × CH3), 2.05 (m, 1 H, CH), 1.58 (m, 2 H, CH2CCH2), 1.16
(d, 9 H, COC(CH3)3), 1.02 (m, 2 H, CH2CCH2); IR (KBr) 2969,
1722, 1657, 1514, 1340, 1286, 1246, 1158, 1033 cm-1; MS (FAB)
m/z 545 (MH+); Anal. (C29H40N2O6S) C, H, N, S.
General Procedure for Vicarious Nucleophilic Substitution.
To a stirred solution of potassium t-butoxide (20 mmol) in DMF
(20 mL) was added a mixture of 29 (or 30; 10 mmol) and ethyl
2-chloropropionate (10 mmol) dropwise at 0 °C. After being stirred
for 10 min at 0 °C, the mixture was quenched with 1 N HCl
solution, diluted with water and extracted with diethyl ether several
times. The combined organic layers were washed with water and
brine, dried over MgSO4, and concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel using
EtOAc/hexanes (1:10) as eluent.
General. All chemical reagents were commercially available.
Melting points were determined on a Büchi Melting Point B-540
apparatus and are uncorrected. Silica gel column chromatography
was performed on silica gel 60, 230–400 mesh, Merck. Proton NMR
spectra were recorded on a JEOL JNM-LA 300 at 300 MHz.
Chemical shifts are reported in ppm units with Me4Si as a reference
standard. Infrared spectra were recorded on a Perkin-Elmer 1710
series FTIR. Mass spectra were recorded on a VG Trio-2 GC-MS.
Elemental analyses were performed with an EA 1110 Automatic
Elemental Analyzer, CE Instruments.
General Procedure for Coupling. A mixture of acid (10 mmol),
the corresponding amine (11 mmol) and 1-(3-dimethylaminopro-
pyl)-3-ethyl-carbodiimide hydrochloride (11 mmol) in CH2Cl2 (20
mL) was stirred overnight at room temperature. The reaction
mixture was filtered off and the filtrate was concentrated. the residue
was purified by flash column chromatography on silica gel using
EtOAc/hexanes as eluent.
N-[2-(3,4-Dimethylbenzyl)-3-pivaloyloxypropyl]-2-[4-(meth-
ylsulfonylamino)phenyl]-2-methylpropionamide (20). Yield 89%,
1
yellow solid, mp ) 126–130 °C; H NMR (CDCl3) δ 7.34 (dd, 2
H, J ) 8.3, 1 Hz, Ar), 7.18 (d, 2 H, J ) 8.3, 1 Hz, Ar), 6.8–7.05
(m, 3 H, Ar), 6.44 (bs, 1 H, NHSO2), 5.60 (t, 1 H, NH), 3.95 (dt,
1 H, CH2OCO), 3.76 (ddd, 1 H, CH2OCO), 3.27 (m, 1 H, CH2NH),
3.08 (m, 1 H, CH2NH), 3.00 (d, 3 H, SO2CH3), 2.45–2.65 (m, 2 H,
CH2Ar), 2.15–2.3 (m, 6 H, 2 × CH3), 2.05 (m, 1 H, CH), 1.53 (s,
6 H, CH3CCH3), 1.19 (d, 9 H, COC(CH3)3); IR (KBr) 2971, 1725,
1646, 1512, 1457, 1336, 1285, 1155 cm-1; MS (FAB) m/z 517
(MH+); Anal. (C28H40N2O5S) C, H, N, S.
Ethyl 2-(3-Fluoro-4-nitrophenyl)propionate (31). Yield 68%,
1
yellow oil; H NMR (CDCl3) δ 8.02 (dd, 1 H, J ) 7.8, 8.0 Hz,
H-5), 7.2–7.3 (m, 2 H, H-2,6), 4.14 (m, 2 H, CO2CH2CH3), 3.78
(q, 1 H, J ) 7.1 Hz, CHCH3), 1.52 (d, 3 H, J ) 7.1 Hz, CHCH3),
1.22 (t, 3 H, J ) 7.08 Hz, CO2CH2CH3).
Ethyl 2-(3-Chloro-4-nitrophenyl)propionate (32). Yield 64%,
1
yellow oil; H NMR (CDCl3) δ 7.87 (d, 1 H, J ) 8.4 Hz, H-5),
7.51 (d, 1 H, J ) 1.8 Hz, H-2), 7.36 (dd, 1 H, J ) 8.4, 1.8 Hz,
H-6), 4.15 (m, 2 H, CO2CH2CH3), 3.77 (q, 1 H, J ) 7.2 Hz,
CHCH3), 1.53 (d, 3 H, J ) 7.2 Hz, CHCH3), 1.24 (t, 3 H, J ) 7.08
Hz, CO2CH2CH3).
General Procedure for Nitro Reduction. Method A: A suspen-
sion of 31 (5 mmol) and 10% Pd-C (500 mg) in EtOH (30 mL)
was hydrogenated under a balloon of hydrogen for 1 h and filtered
through celite. The filtrate was concentrated in vacuo and the residue
was purified by flash column chromatography on silica gel using
EtOAc/hexanes (1:4) as eluent to afford 33.
N-[2-(3,4-Dimethylbenzyl)-3-pivaloyloxypropyl]-2-[3-fluoro-
4-(methylsulfonylamino)phenyl]-2-methylpropionamide (21).
Yield 82%, white solid, mp ) 63–65 °C; 1H NMR (CDCl3) δ 7.52
(dt, 1 H, H-5), 6.8–7.2 (m, 5 H, Ar), 5.74 (t, 1 H, NH), 4.01 (dt, 1
H, CH2OCO), 3.77 (ddd, 1 H, CH2OCO), 3.28 (m, 1 H, CH2NH),
2.95–3.15 (m, 4 H, CH2NH and SO2CH3), 2.45–2.65 (m, 2 H,
CH2Ar), 2.15–2.3 (m, 6 H, 2 × CH3), 2.05 (m, 1 H, CH), 1.52 (s,
6 H, CH3CCH3), 1.20 (d, 9 H, COC(CH3)3); IR (KBr) 2972, 1721,
1652, 1584, 1511, 1456, 1336, 1285, 1159 cm-1; MS (FAB) m/z
535 (MH+); Anal. (C28H39FN2O5S) C, H, N, S.
Method B: A suspension of 32 (5 mmol) and activated iron (0.28
g, 5 mmol) in acetic acid (30 mL) was heated at 90 °C for 1 min.
After being cooled at room temperature, the mixture was diluted
with EtOH and filtered and the filtrate was concentrated in vacuo.
The residue was purified by flash column chromatography on silica
gel using EtOAc/hexanes (1:4) as eluent to afford 34.
N-[2-(3,4-Dimethylbenzyl)-3-pivaloyloxypropyl]-2-[3-methoxy-
4-(methylsulfonylamino)phenyl]-2-methylpropionamide (22).
1
Yield 84%, white solid, mp ) 100–103 °C; H NMR (CDCl3) δ
7.48 (dd, 1 H, J ) 8.3, 2 Hz, H-5), 6.8–7.05 (m, 5 H, Ar), 6.74
(bs, 1 H, NHSO2), 5.61 (t, 1 H, NH), 3.95 (ddd, 1 H, CH2OCO),
3.86 (s, 3 H, OCH3), 3.75 (ddd, 1 H, CH2OCO), 3.26 (m, 1 H,
CH2NH), 3.06 (m, 1 H, CH2NH), 2.96 (d, 3 H, SO2CH3), 2.45–2.65
(m, 2 H, CH2Ar), 2.15–2.3 (m, 6 H, 2 × CH3), 2.05 (m, 1 H, CH),
1.54 (s, 6 H, CH3CCH3), 1.19 (d, 9 H, COC(CH3)3); IR (KBr) 2969,
1722, 1653, 1512, 1458, 1336, 1285, 1158, 1033 cm-1; MS (FAB)
m/z 547 (MH+); Anal. (C29H42N2O6S) C, H, N, S.
Ethyl 2-(4-Amino-3-fluorophenyl)propionate (33). Yield 94%,
1
a colorless oil; H NMR (CDCl3) δ 6.96 (dd, 1 H, J ) 1.7, 11.9
Hz, H-2), 6.87 (dd, 1 H, J ) 1.7, 8.3 Hz, H-6), 6.71 (dd, 1 H, J )
8.3, 11.9 Hz, H-5), 4.11 (m, 2 H, CO2CH2CH3), 3.58 (q, 1 H, J )
7.1 Hz, CHCH3), 3.45 (bs, 2 H, NH2), 1.43 (d, 3 H, J ) 7.1 Hz,
CHCH3), 1.20 (t, 3 H, J ) 7.05 Hz, CO2CH2CH3).
N-[2-(3,4-Dimethylbenzyl)-3-pivaloyloxypropyl]-1-[4-(meth-
ylsulfonylamino)phenyl]cyclopropanecarboxamide (26). Yield
80%, white solid, mp ) 54–56 °C; 1H NMR (CDCl3) δ 7.38 (d, 2
H, J ) 8.3 Hz, Ar), 7.21 (d, 2 H, J ) 8.3 Hz, Ar), 6.75–7.05 (m,
3 H, Ar), 6.37 (bs, 1 H, NHSO2), 5.56 (bs, 1 H, NH), 3.93 (m, 1
H, CH2OCO), 3.76 (m, 1 H, CH2OCO), 3.27 (m, 1 H, CH2NH),
2.95–3.1 (m, 4 H, SO2CH3 and CH2NH), 2.4–2.6 (m, 2 H, CH2Ar),
2.15–2.3 (m, 6 H, 2 × CH3), 2.05 (m, 1 H, CH), 1.58 (m, 2 H,
CH2CCH2), 1.17 (s, 9 H, COC(CH3)3), 1.00 (m, 2 H, CH2CCH2);
IR (KBr) 2969, 1723, 1644, 1517, 1333, 1286, 1156 cm-1; MS
(FAB) m/z 515 (MH+); Anal. (C28H38N2O5S) C, H, N, S.
N-[2-(3,4-Dimethylbenzyl)-3-pivaloyloxypropyl]-1-[3-fluoro-
4-(methylsulfonylamino)phenyl]cyclopropanecarboxamide (27).
Yield 82%, white solid, mp ) 64–66 °C; 1H NMR (CDCl3) δ 7.52
(dt, 1 H, H-5), 6.8–7.2 (m, 5 H, Ar), 6.38 (bs, 1 H, NHSO2), 5.57
(bs, 1 H, NH), 3.95 (m, 1 H, CH2OCO), 3.76 (m, 1 H, CH2OCO),
Ethyl 2-(4-Amino-3-chlorophenyl)propionate (34). Yield 88%,
yellow oil; 1H NMR (CDCl3) δ 7.20 (d, 1 H, J ) 2 Hz, H-2), 7.00
(dd, 1 H, J ) 2, 8.1 Hz, H-6), 6.71 (d, 1 H, J ) 8.1 Hz, H-5), 4.11
(m, 2 H, CO2CH2CH3), 4.00 (bs, 2 H, NH2), 3.56 (q, 1 H, J ) 7.1
Hz, CHCH3), 1.44 (d, 3 H, J ) 7.1 Hz, CHCH3), 1.21 (t, 3 H, J )
7.1 Hz, CO2CH2CH3).
General Procedure for Mesylation. A cooled solution of 33
(or 34; 4 mmol) in pyridine (10 mL) at 0 °C was treated dropwise
with methanesulfonyl chloride (6 mmol) over 10 min and stirred
for 1 h at room temperature. After aqueous workup, the residue
was purified by flash column chromatography on silica gel using
EtOAc/hexanes (1:2) as eluent.
Ethyl 2-[3-Fluoro-4-(methylsulfonylamino)phenyl]propionate
1
(35). Yield 91%, white solid, mp ) 81 °C; H NMR (CDCl3) δ
7.50 (t, 1 H, J ) 8.3 Hz, H-5), 7.0–7.1 (m, 2 H, H-2,6), 6.55 (bs,

64 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 1
Ryu et al.
1 H, NHSO2), 4.12 (m, 2 H, CO2CH2CH3), 3.68 (q, 1 H, J ) 7.1
Hz, CHCH3), 3.02 (s, 3 H, SO2CH3), 1.48 (d, 3 H, J ) 7.1 Hz,
CHCH3), 1.22 (t, 3 H, J ) 7.1 Hz, CO2CH2CH3).
2 H, CH2OH), 3.43 (q, 1 H, J ) 7.1 Hz, CHCH3), 3.02 (s, 3 H,
SO2CH3), 2.88 (dd of AB, 1 H, J ) 6.8, 13.7 Hz, CH2Ph), 2.80
(dd of AB, 1 H, J ) 7.9, 13.7 Hz, CH2Ph), 2.47 (t, 1 H, J ) 5.1
Hz, OH), 1.43 (d, 3 H, J ) 7.1 Hz, CHCH3).
General Procedure for Amide Hydrolysis. A solution of 37
(or 38; 1 mmol) in 3 N H2SO4 (4 mL) and 1,4-dioxane (4 mL) was
heated to 100 °C for 5 h and cooled to room temperature. The
solution was diluted with water and extracted with CH2Cl2 several
times. The combined organic layers were washed with water, dried
over MgSO4, and concentrated in vacuo to afford 39 (or 40) in
75–90% yields.
(2R)-[3-Fluoro-4-(methylsulfonylamino)phenyl]propionic Acid
(39R). [R] ) -29.25 (c 1.00, CHCl3). The spectra are identical to
those of 35.
(2S)-[3-Fluoro-4-(methylsulfonylamino)phenyl]propionic Acid
(39S). [R] ) +29.76 (c 1.00, CHCl3). The spectra are identical to
those of 35.
Ethyl 2-[3-Chloro-4-(methylsulfonylamino)phenyl]propionate
1
(36). Yield 90%, colorless oil; H NMR (CDCl3) δ 7.60 (d, 1 H,
J ) 8.4 Hz, H-5), 7.40 (d, 1 H, J ) 2 Hz, H-2), 7.25 (dd, 1 H, J
) 8.4, 2 Hz, H-6), 6.78 (bs, 1 H, NHSO2), 4.14 (m, 2 H,
CO2CH2CH3), 3.67 (q, 1 H, J ) 7.1 Hz, CHCH3), 3.02 (s, 3 H,
SO2CH3), 1.49 (d, 3 H, J ) 7.1 Hz, CHCH3), 1.23 (t, 3 H, J ) 7.1
Hz, CO2CH2CH3).
General Procedure for Ester Hydrolysis. A solution of 35 (or
36; 2 mmol) in H2O and THF (1:2, 30 mL) was treated with lithium
hydroxide (6 mmol) and stirred for 4 h at room temperature. The
mixture was diluted with H2O and CH2Cl2, acidified with 1 N HCl
solution, and extracted with CH2Cl2 several times. The combined
organic layers were washed with water and brine, dried over
MgSO4, and concentrated in vacuo. The residue was crystallized
from diethyl ether and n-hexane.
(2R)-[3-Chloro-4-(methylsulfonylamino)phenyl]propionic Acid
(40R). [R] ) +14.80 (c 1.00, CHCl3). The spectra are identical to
those of 36.
2-[3-Fluoro-4-(methylsulfonylamino)phenyl]propionic Acid
1
(6). Yield 97%, white solid, mp ) 120 °C; H NMR (CDCl3) δ
7.52 (t, 1 H, J ) 8.04 Hz, H-5), 7.1–7.15 (m, 2 H, H-2,6), 6.60
(bs, 1 H, NHSO2), 3.73 (q, 1 H, J ) 7.1 Hz, CHCH3), 3.03 (s, 3
H, SO2CH3), 1.51 (d, 3 H, J ) 7.1 Hz, CHCH3).
(2S)-[3-Chloro-4-(methylsulfonylamino)phenyl]propionic Acid
(40S). [R] ) +19.62 (c 1.00, CHCl3). The spectra are identical to
those of 36.
2-[3-Chloro-4-(methylsulfonylamino)phenyl]propionic Acid
Dibenzyl (2S)-2-Hydroxybutanedioate (41). A mixture of
L-malic acid (6.7 g, 50 mmol), benzyl alcohol (10.34 mL, 100
mmol), and a few crystals of p-toluenesulfonic acid in toluene (50
mL) under a Dean–Stark trap was refluxed overnight. After cooling
to ambient temperature, the mixture was evaporated under reduced
pressure. The residue was purified by flash column chromatography
on silica gel with EtOAc/hexanes (1:4) as eluent to give 41 as an
1
(7). Yield 92%, pink solid, mp ) 133–135 °C; H NMR (CDCl3)
δ 10.19 (bs, 1 H, CO2H), 7.60 (d, 1 H, J ) 8.4 Hz, H-5), 7.41 (d,
1 H, J ) 1.8 Hz, H-2), 7.26 (dd, 1 H, J ) 8.4, 1.8 Hz, H-6), 6.91
(bs, 1 H, NHSO2), 3.72 (q, 1 H, J ) 7.1 Hz, CHCH3), 3.02 (s, 3
H, SO2CH3), 1.51 (d, 3 H, J ) 7.1 Hz, CHCH3).
General Procedure for Coupling with L-Phenylalaniol. A
cooled solution of 6 (or 7; 1 mmol) and L-phenyl alaninol (1.1
mmol) in CH2Cl2 (10 mL) at 0 °C was treated with 1-(3-
dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (1.5 mmol)
followed by 1-hydroxybenzotriazole (1.5 mmol) and triethylamine
(1.5 mmol). After being stirred for 6 h at room temperature, the
reaction mixture was diluted with CH2Cl2, washed with H2O, dried
over MgSO4, filtered, and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel using EtOAc
as eluent to afford 37 (or 38) in 95–98% yield.
1
oil (13.83 g, 88%); H NMR (CDCl3) δ 7.25–7.35 (m, 10 H, 2 ×
Ph), 5.17 (s, 2 H, CH2Ph), 5.10 (s, 2 H, CH2Ph), 4.54 (m, 1 H,
CHOH), 3.30 (d, 1 H, J ) 5.4 Hz, OH), 2.87 (m, 2 H, CH2CO2Bn).
General Procedure for Alkylation. A stirred solution of 41 (15
mmol) in THF (20 mL) was cooled to -78 °C and treated dropwise
with LiHMDS (1 M in THF, 30 mmol) and HMPA (30 mmol).
After being stirred for 30 min at -78 °C, the mixture was treated
with benzyl halide (15 mmol) in THF (10 mL) and stirred for 30
min at the same temperature. The reaction mixture was quenched
by the slow addition of a saturated aqueous solution of ammonium
chloride and extracted with ether several times. The combined
organic layers were washed with H2O and brine, dried over MgSO4,
and concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel with EtOAc/hexanes (1:10) as eluent.
Dibenzyl (2R,3S)-2-Benzyl-3-hydroxybutanedioate (42). Yield
55%, white solid, mp ) 65–66 °C; 1H NMR (CDCl3) δ 7.15–7.35
(m, 15 H, 3 × Ph), 5.00 (dd of AB, 4 H, 2 × CH2Ph), 4.13 (d, 1
H, J ) 2.5 Hz, CHOH), 3.15–3.25 (m, 2 H, CH2Ph), 3.00 (m, 1 H,
CHCO2Bn).
N-[(1S)-1-Benzyl-2-hydroxyethyl]-(2R)-2-[3-fluoro-4-(methyl-
sulfonylamino)phenyl]propionamide (37R). White solid, mp )
1
164∼166 °C, [R] ) -25.48 (c 1.00, MeOH); H NMR (CD3OD)
δ 7.33 (t, 1 H, J ) 8.5 Hz, H-5), 6.9–7.12 (m, 7 H, H-2,6 and Ph),
4.12 (m, 1 H, CHNH), 3.5–3.6 (m, 3 H, CHCH3 and CH2OH),
2.98 (s, 3 H, SO2CH3), 2.88 (dd, 1 H, J ) 5.1, 14 Hz, CH2Ph),
2.71 (dd, 1 H, J ) 9.3, 14 Hz, CH2Ph), 1.36 (d, 3 H, J ) 7.05 Hz,
CHCH3).
N-[(1S)-1-Benzyl-2-hydroxyethyl]-(2S)-2-[3-fluoro-4-(methyl-
sulfonylamino)phenyl]propionamide (37S). White solid, mp )
150–153 °C, [R] ) -20.36 (c 1.00, MeOH); 1H NMR (CD3OD) δ
7.36 (t, 1 H, J ) 8.5 Hz, H-5), 7.0–7.28 (m, 7 H, H-2,6 and Ph),
4.07 (m, 1 H, CHNH), 3.56 (q, 1 H, J ) 7.3 Hz, CHCH3), 3.48
(dd, 2 H, J ) 1.2, 5.1 Hz, CH2OH), 2.9–3.0 (m, 4 H, SO2CH3 and
CH2Ph), 2.71 (dd, 1 H, J ) 9, 14 Hz, CH2Ph), 1.27 (d, 3 H, J )
7.05 Hz, CHCH3).
Dibenzyl (2R,3S)-2-(4-t-Butylbenzyl)-3-hydroxybutanedioate
1
(43). Yield 68%, white solid, mp ) 37–38 °C; H NMR (CDCl3)
δ 7.12–7.35 (m, 14 H, 2 × Ph and Ar), 5.02 (s, 4 H, 2 × CH2Ph),
4.17 (dd, 1 H, J ) 2.9, 7.1 Hz, CHOH), 3.12–3.28 (m, 3 H, CH2Ph
and OH), 2.97 (dd, 1 H, J ) 9, 13.2 Hz CHCO2Bn), 1.29 (s, 9 H,
C(CH3)3).
N-[(1S)-1-Benzyl-2-hydroxyethyl]-(2R)-2-[3-chloro-4-(meth-
ylsulfonylamino)phenyl]propionamide (38R). White solid, mp )
General Procedure for Ester Reduction. To a suspension of
lithium aluminum hydride (20 mmol) in THF (10 mL) was added
dropwise a solution of 42 (or 43; 5 mmol) in THF (20 mL). After
being stirred for 3 h at room temperature, the reaction mixture was
cooled in an ice-bath, quenched with H2O, 15% NaOH (aq), and
H2O, successively, and stirred for 1 h. The suspension was filtered
by washing with EtOAc and the combined filtrates were concen-
trated in vacuo. The residue was purified by flash column
chromatography on silica gel with EtOAc as eluent.
(2S,3S)-3-Benzyl-1,2,4-butanetriol (44). Yield 56%, colorless
oil; 1H NMR (CDCl3) δ 7.15–7.35 (m, 5 H, Ph), 3.6–3.8 (m, 5 H,
2 × CH2OH and CHOH), 2.73 (ddd of AB, 2 H, CH2Ar), 2.46 (bs,
3 H, OH), 1.93 (m, 1 H, CH).
1
167–169 °C, [R] ) +39.5 (c 1.00, CHCl3); H NMR (CDCl3) δ
7.54 (d, 1 H, J ) 8.4 Hz, H-5), 7.2–7.3 (m, 4 H), 7.0–7.06 (m, 3
H), 6.76 (bs, 1 H, NHSO2), 5.55 (d, 1 H, J ) 7.7 Hz, CHNH),
4.16 (m, 1 H, CHNH), 3.55–3.75 (m, 2 H, CH2OH), 3.43 (q, 1 H,
J ) 7.1 Hz, CHCH3), 3.02 (s, 3 H, SO2CH3), 2.85 (dd of AB, 1 H,
J ) 6.4, 13.7 Hz, CH2Ph), 2.72 (dd of AB, 1 H, J ) 8.1, 13.7 Hz,
CH2Ph), 2.43 (t, 1 H, J ) 5.3 Hz, OH), 1.43 (d, 3 H, J ) 7.1 Hz,
CHCH3).
N-[(1S)-1-Benzyl-2-hydroxyethyl]-(2S)-2-[3-chloro-4-(methyl-
sulfonylamino)phenyl]propionamide (38S). White solid, mp )
1
149–151 °C, [R] ) -43.8 (c 1.00, CHCl3); H NMR (CDCl3) δ
7.56 (d, 1 H, J ) 8.4 Hz, H-5), 7.34 (d, 1 H, J ) 2 Hz, H-2),
7.22–7.3 (m, 3 H), 7.1–7.15 (m, 3 H), 6.76 (bs, 1 H, NHSO2), 5.64
(d, 1 H, J ) 6.8 Hz, CHNH), 4.12 (m, 1 H, CHNH), 3.55–3.7 (m,
(2S,3S)-3-(4-t-Butylbenzyl)-1,2,4-butanetriol (45). Yield 55%,
1
colorless oil; H NMR (CDCl3) δ 7.31 (bd, 2 H, Ar), 7.12 (bd, 2
H, Ar), 3.6–3.8 (m, 5 H, 2 × CH2OH and CHOH), 3.19 (bs, 1 H,

Stereospecific High-Affinity TRPV1 Antagonists
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 1 65
OH), 2.76 (dd of AB, 1 H, CH2Ar), 2.70 (bs, 2 H, OH), 2.62 (dd
of AB, 1 H, CH2Ar), 1.92 (m, 1 H, CH), 1.30 (s, 9 H, C(CH3)3).
General Procedure for Acetonidation. A mixture of 44 (or 45;
4 mmol) and p-toluenesulfonic acid (10 wt%) in acetone (10 mL)
was stirred for 3 h at room temperature. The mixture was neutralized
with solid sodium bicarbonate and filtered, and the filtrate was
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel with EtOAc/hexanes (1:2) as eluent.
CH2N3), 2.56–2.7 (ddd of AB, 2 H, CH2Ar), 2.04 (m, 1 H, CH),
1.31 (s, 9 H, C(CH3)3).
General Procedure for Pivaloylation. A cooled solution of 52
(or 53; 1 mmol) in CH2Cl2 (10 mL) at 0 °C was treated with
pyridine (4 mmol) and pivaloyl chloride (2 mmol) and stirred for
30 min at room temperature. The reaction mixture was concentrated
in vacuo and the residue was purified by flash column chromatog-
raphy on silica gel with EtOAc/hexanes (1:4) as eluent.
(2S)-3-Azido-2-benzylpropyl Pivalate (54). Yield 80%, color-
(2S)-2-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-3-phenyl-1-pro-
panol (46). Yield 76%, colorless oil; 1H NMR (CDCl3) δ 7.15–7.35
(m, 5 H, Ph), 4.10 (m, 1 H, CHO), 3.95 (dd, 1 H, CH2O), 3.74 (dd,
1 H, CH2O), 3.64 (m, 2 H, CH2OH), 2.5–2.7 (m, 2 H, CH2Ar),
1.98 (m, 1 H, CH), 1.42 (s, 3 H, CH3), 1.35 (s, 3 H, CH3).
1
less oil; H NMR (CDCl3) δ 7.15–7.35 (m, 5 H, Ph), 4.09 (dd of
AB, 1 H, CH2OCO), 3.99 (dd of AB, 1 H, CH2OCO), 3.28–3.40
(septet, 2 H, CH2N3), 2.68 (d, 2 H, J ) 7.3 Hz, CH2Ar), 2.18 (m,
1 H, CH), 1.23 (s, 9 H, COC(CH3)3).
(2S)-3-Azido-2-(4-t-butylbenzyl)propyl Pivalate (55). Yield
(2S)-2-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-3-(4-t-butylphe-
nyl)-1-propanol (47). Yield 82%, colorless oil; 1H NMR (CDCl3)
δ 7.25 (bd, 2 H, Ar), 7.06 (bd, 2 H, Ar), 4.06 (m, 1 H, CHO), 3.89
(dd, 1 H, CH2O), 3.52–3.7 (m, 2 H, CH2O and CH2OH), 2.43–2.58
(m, 2 H, CH2Ar), 1.94 (m, 1 H, CH), 1.37 (s, 3 H, CH3), 1.31 (s,
3 H, CH3), 1.26 (s, 9 H, C(CH3)3).
1
82%, colorless oil; H NMR (CDCl3) δ 7.32 (bd, 2 H, Ar), 7.08
(bd, 2 H Ar), 4.08 (dd of AB, 1 H, CH2OCO), 3.99 (dd of AB, 1
H, CH2OCO), 3.28–3.40 (septet, 2 H, CH2N3), 2.65 (d, 2 H, J )
7.3 Hz, CH2Ar), 2.20 (m, 1 H, CH), 1.31 (s, 9 H, C(CH3)3), 1.23
(s, 9 H, COC(CH3)3).
(2S)-2-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-3-phenylpropyl
Pivalate (61). The compound was prepared from 46 by following
the general procedure for pivaloylation. Yield 85%, colorless oil;
1H NMR (CDCl3) δ 7.15–7.35 (m, 5 H, Ph), 4.05–4.16 (m, 3 H,
CH2OCO and CHO), 3.96 (dd, 1 H, CH2O), 3.68 (t, 1 H, J ) 7.5
Hz, CH2O), 2.68 (d, 2 H, J ) 7.3 Hz, CH2Ar), 2.15 (m, 1 H, CH),
1.41 (s, 3 H, CH3), 1.34 (s, 3 H, CH3), 1.23 (s, 9 H, C(CH3)3).
(2S)-2-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-3-(4-t-butylphe-
nyl)propyl Pivalate (62). The compound was prepared from 47
by following the general procedure for pivaloylation. Yield 92%,
General Procedure for Azide Formation. To a stirred solution
of 46 (or 47; 3 mmol), triphenylphosphine (6 mmol), and diethyl
azodicarboxylate (6 mmol) in THF (10 mL) was added a solution
of diphenylphosphoryl azide (6 mmol) in THF (10 mL) at room
temperature. The reaction mixture was stirred for 2 h, and the
reaction mixture was concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel with EtOAc/
heaxanes (1:10) as eluent.
(4S)-4-[(1S)-2-Azido-1-benzylethyl]-2,2-dimethyl-1,3-diox-
olane (48). Yield 88%, colorless oil; 1H NMR (CDCl3) δ 7.15–7.35
(m, 5 H, Ph), 3.95–4.16 (m, 2 H, CHO and CH2O), 3.60 (dd, 1 H,
CH2O), 3.50 (dd, 1 H, CH2N3), 3.30 (dd, 1 H, CH2N3), 2.53–2.70
(ddd of AB, 2 H, CH2Ar), 1.97 (m, 1 H, CH), 1.40 (s, 3 H, CH3),
1.36 (s, 3 H, CH3).
1
colorless oil; H NMR (CDCl3) δ 7.30 (bd, 2 H, Ar), 7.07 (bd, 2
H, Ar), 4.04–4.15 (m, 3 H, CH2OCO and CHO), 3.96 (dd, 1 H,
CH2O), 3.65 (t, 1 H, J ) 7.5 Hz, CH2O), 2.64 (d, 2 H, J ) 7.3 Hz,
CH2Ar), 2.07 (m, 1 H, CH), 1.41 (s, 3 H, CH3), 1.34 (s, 3 H, CH3),
1.30 (s, 9 H, C(CH3)3), 1.22 (s, 9 H, COC(CH3)3).
(4S)-4-[(1S)-2-Azido-1-(4-t-butylbenzyl)ethyl]-2,2-dimethyl-
1,3-dioxolane (49). Yield 90%, colorless oil; 1H NMR (CDCl3) δ
7.32 (bd, 2 H, Ar), 7.09 (bd, 2 H, Ar), 4.06 (dd, 1 H, CHO), 3.97
(dd, 1 H, CH2O), 3.60 (dd, 1 H, CH2O), 3.51 (dd, 1 H, CH2N3),
3.32 (dd, 1 H, CH2N3), 2.5–2.70 (ddd of AB, 2 H, CH2Ar), 1.96
(m, 1 H, CH), 1.40 (s, 3 H, CH3), 1.36 (s, 3 H, CH3), 1.31 (s, 9 H,
C(CH3)3).
General Procedure for Aldehyde Formation. A solution of
48 (or 49; 2 mmol) in ether and THF (5:3, 20 mL) was treated
with periodic acid (10 mmol). After being stirred for 5 h, the
reaction mixture was concentrated in vacuo and the residue was
purified by flash column chromatography on silica gel with EtOAc/
hexanes (1:4) as eluent.
(2S)-2-Benzyl-3-oxopropyl Pivalate (63). The compound was
prepared from 61 by following the general procedure for adehyde
1
formation. Yield 98%, colorless oil; H NMR (CDCl3) δ 9.76 (d,
1 H, J ) 1.2 Hz, CHO), 7.15–7.35 (m, 5 H, Ph), 4.34 (dd, 1 H,
CH2OCO), 4.20 (dd, 1 H, CH2OCO), 3.10 (dd, 1 H, CH2Ar), 2.92
(m, 1 H, CH), 2.79 (dd, 1 H, CH2Ar), 1.19 (s, 9 H, C(CH3)3).
(2S)-2-(4-t-Butylbenzyl)-3-oxopropyl Pivalate (64). The com-
pound was prepared from 62 by following the general procedure
for adehyde formation. Yield 98%, colorless oil; 1H NMR (CDCl3)
δ 9.76 (s, 1 H, CHO), 7.32 (bs, 2 H, Ar), 7.10 (bs, 2 H, Ar), 4.32
(dd, 1 H, CH2OCO), 4.22 (dd, 1 H, CH2OCO), 3.06 (dd, 1 H,
CH2Ar), 2.90 (m, 1 H, CH), 2.78 (dd, 1 H, CH2Ar), 1.30 (s, 9 H,
C(CH3)3), 1.19 (s, 9 H, COC(CH3)3).
(2S)-3-Azido-2-benzyl-propanal (50). Yield 98%, colorless oil;
1H NMR (CDCl3) δ 9.76 (s, 1 H, CHO), 7.15–7.35 (m, 5 H, Ph),
3.54 (m, 2 H, CH2N3), 3.08 (m, 1 H, CHCHO), 2.75–2.88 (m, 2
H, CH2Ar).
(2S)-3-Azido-2-(4-t-butylbenzyl)propanal (51). Yield 98%,
colorless oil; 1H NMR (CDCl3) δ 9.77 (d, 1 H, J ) 0.7 Hz, CHO),
7.32 (bd, 2 H, Ar), 7.11 (bd, 2 H, Ar), 3.54 (d, 2 H, J ) 4.9 Hz,
CH2N3), 3.05 (m, 1 H, CHCHO), 2.75–2.85 (m, 2 H, CH2Ar), 1.30
(s, 9 H, C(CH3)3).
(2R)-2-Benzyl-3-hydroxypropyl Pivalate (65). The compound
was prepared from 63 by following the general procedure for
1
adehyde reduction. Yield 80%, colorless oil; H NMR (CDCl3) δ
7.15–7.35 (m, 5 H, Ph), 4.22 (dd, 1 H, CH2OCO), 4.04 (dd, 1 H,
CH2OCO), 3.4–3.63 (m, 2 H, CH2OH), 2.58–2.74 (ddd of AB, 2
H, CH2Ar), 2.14 (m, 1 H, CH), 1.23 (s, 9 H, C(CH3)3).
(2R)-2-(4-t-Butylbenzyl)-3-hydroxypropyl Pivalate (66). The
compound was prepared from 64 by following the general procedure
for adehyde reduction. Yield 90%, colorless oil; 1H NMR (CDCl3)
δ 7.31 (bd, 2 H, Ar), 7.11 (bd, 2 H, Ar), 4.22 (dd, 1 H, CH2OCO),
4.05 (dd, 1 H, CH2OCO), 3.4–3.64 (m, 2 H, CH2OH), 2.55–2.7
(ddd of AB, 2 H, CH2Ar), 2.14 (m, 1 H, CH), 1.31 (s, 9 H,
C(CH3)3), 1.23 (s, 9 H, COC(CH3)3).
(2R)-3-Azido-2-benzylpropyl Pivalate (67). The compound was
prepared from 65 by following the general procedure for azido
formation. Yield 87%, colorless oil; 1H NMR (CDCl3) δ 7.15–7.35
(m, 5 H, Ph), 4.09 (dd, 1 H, CH2OCO), 3.99 (dd, 1 H, CH2OCO),
3.34 (septet, 2 H, CH2N3), 2.68 (d, 2 H, J ) 7.3 Hz, CH2Ar), 2.21
(m, 1 H, CH), 1.23 (s, 9 H, C(CH3)3).
General Procedure for Aldehyde Reduction. A cooled solution
of 50 (or 51; 2 mmol) in MeOH (15 mL) at 0 °C was treated with
sodium borohydride (4 mmol) and stirred for 30 min. The reaction
mixture was concentrated in vacuo. The residue was treated with
H2O (30 mL) and extracted with CH2Cl2 several times. The organic
layer was washed with brine, dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel with EtOAc/heaxanes (1:2) as eluent.
(2S)-3-Azido-2-benzyl-1-propanol (52). Yield 72%, colorless
1
oil; H NMR (CDCl3) δ 7.15–7.35 (m, 5 H, Ph), 3.55–3.72 (m, 2
H, CH2OH), 3.33–3.47 (ddd of AB, 2 H, CH2N3), 2.60–2.74 (ddd
of AB, 2 H, CH2Ar), 2.00 (m, 1 H, CH).
(2R)-3-Azido-2-(4-t-butylbenzyl)propyl Pivalate (68). The
compound was prepared from 66 by following the general procedure
for azide formation. Yield 84%, colorless oil; 1H NMR (CDCl3) δ
7.32 (bd, 2 H, Ar), 7.08 (bd, 2 H, Ar), 4.09 (dd, 1 H, CH2OCO),
3.99 (dd, 1 H, CH2OCO), 3.34 (septet, 2 H, CH2N3), 2.65 (d, 2 H,
(2S)-3-Azido-2-(4-t-butylbenzyl)-1-propanol (53). Yield 89%,
1
colorless oil; H NMR (CDCl3) δ 7.32 (bd, 2 H, Ar), 7.11 (bd, 2
H, Ar), 3.56–3.73 (m, 2 H, CH2OH), 3.33–3.48 (ddd of AB, 2 H,

66 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 1
Ryu et al.
J ) 7.3 Hz, CH2Ar), 2.20 (m, 1 H, CH), 1.31 (s, 9 H, C(CH3)3),
1.23 (s, 9 H, COC(CH3)3)
3.34 (ddd, 1 H, CH2NH), 2.95–3.08 (m, 4 H, CH2NH and SO2CH3),
2.53 (ddd of AB, 2 H, CH2Ar), 2.12 (m, 1 H, CH), 1.47 (d, 3 H,
J ) 7.1 Hz, CHCH3), 1.30 (s, 9 H, C(CH3)3), 1.22 (s, 9 H,
COC(CH3)3); IR (KBr) 3296, 2964, 1722, 1652, 1498, 1333, 1263,
General Procedure for Coupling. A suspension of azide (1
mmol) and 10% palladium on carbon (100 mg) in MeOH (5 mL)
was hydrogenated under a balloon of hydrogen for 2 h. The mixture
was filtered through celite and the filtrate was concentrated in vacuo
to give the corresponding amine. The amine was dissolved in
CH2Cl2 (5 mL) and treated with chiral acid (1 mmol) and 1-(3-
dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (1.1 mmol).
After being stirred for 12 h at room temperature, the reaction
mixture was filtered and the filtrate was concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel
using EtOAc/hexanes as eluent.
N-[(2S)-2-Benzyl-3-(pivaloyloxy)propyl]-(2R)-2-[3-fluoro-4-
(methylsulfonylamino)phenyl]propionamide (56). Yield 88%,
white solid, mp ) 40–42 °C, [R] ) -10.5 (c 0.5, CHCl3); 1H NMR
(CDCl3) δ 7.51 (t, 1 H, J ) 8.25 Hz, H-5), 7.06–7.32 (m, 7 H),
6.50 (bs, 1 H, NHSO2), 5.93 (bt, 1 H, NHCO), 4.05 (dd, 1 H, J )
4, 11.5 Hz, CH2OCO), 3.76 (dd, 1 H, J ) 5, 11.5 Hz, CH2OCO),
3.45 (q, 1 H, J ) 7.1 Hz, CHMe), 3.36 (dt, 1 H, CH2NH), 2.9–3.05
(m, 4 H, CH2NH and SO2CH3), 2.58 (d, 2 H, J ) 7.5 Hz, CH2Ph),
2.09 (m, 1 H, CH), 1.47 (d, 3 H, J ) 7.1 Hz, CH3), 1.22 (s, 9 H,
C(CH3)3); IR (KBr) 3287, 2972, 1723, 1654, 1511, 1333, 1284,
1157 cm-1; MS (FAB) m/z 493 (MH+); Anal. (C25H33FN2O5S) C,
H, N, S.
1159, 1027 cm-1
;
MS (FAB) m/z 566 (MH+); Anal.
(C29H41ClN2O5S) C, H, N, S.
N-[(2R)-2-Benzyl-3-(pivaloyloxy)propyl]-(2R)-2-[3-fluoro-4-
(methylsulfonylamino)phenyl]propionamide (69). Yield 89%,
white solid, mp ) 92∼94 °C, [R] ) -8.5 (c 0.5, CHCl3). The
spectra are identical to those of 57. MS (FAB) m/z 493 (MH+);
Anal. (C25H33FN2O5S) C, H, N, S.
N-[(2R)-2-Benzyl-3-(pivaloyloxy)propyl]-(2S)-2-[3-fluoro-4-
(methylsulfonylamino)phenyl]propionamide (70). Yield 87%,
white solid, mp ) 40–42 °C, [R] ) +8.2 (c 0.5, CHCl3). The
spectra are identical to those of 56. MS (FAB) m/z 493 (MH+);
Anal. (C25H33FN2O5S) C, H, N, S.
N-[(2R)-2-(4-t-Butylbenzyl)-3-(pivaloyloxy)propyl]-(2R)-2-[3-
fluoro-4-(methylsulfonylamino)phenyl]propionamide (71). Yield
90%, white solid, mp ) 43–45 °C, [R] ) -6.7 (c 1.0, CHCl3).
The spectra are identical to those of 59. MS (FAB) m/z 549 (MH+);
Anal. (C29H41FN2O5S) C, H, N, S.
N-[(2R)-2-(4-t-Butylbenzyl)-3-(pivaloyloxy)propyl]-(2S)-2-[3-
fluoro-4-(methylsulfonylamino)phenyl]propionamide (72). Yield
90%, white solid, mp ) 44–46 °C, [R] ) +6.6 (c 1.0, CHCl3).
The spectra are identical to those of 58. MS (FAB) m/z 549 (MH+);
Anal. (C29H41FN2O5S) C, H, N, S.
N-[(2S)-2-Benzyl-3-(pivaloyloxy)propyl]-(2S)-2-[3-fluoro-4-
(methylsulfonylamino)phenyl]propionamide (57). Yield 86%,
white solid, mp ) 92∼94 °C, [R] ) +6.8 (c 0.5, CHCl3); 1H NMR
(CDCl3) δ 7.52 (t, 1 H, J ) 8.25 Hz, H-5), 7.06–7.32 (m, 7 H),
6.52 (bs, 1 H, NHSO2), 5.92 (bt, 1 H, NHCO), 4.08 (dd, 1 H, J )
4, 11.5 Hz, CH2OCO), 3.79 (dd, 1 H, J ) 5, 11.5 Hz, CH2OCO),
3.46 (q, 1 H, J ) 7.1 Hz, CHMe), 3.33 (dt, 1 H, CH2NH), 3.03
(dt, 1 H, CH2NH), 3.00 (s, 3 H, SO2CH3), 2.48–2.62 (m, 2 H,
CH2Ph), 2.13 (m, 1 H, CH), 1.47 (d, 3 H, J ) 7.1 Hz, CH3), 1.22
(s, 9 H, C(CH3)3); IR (KBr) 3287, 2972, 1718, 1658, 1508, 1330,
N-[(2R)-2-(4-t-Butylbenzyl)-3-(pivaloyloxy)propyl]-(2S)-2-[3-
chloro-4-(methylsulfonylamino)phenyl]propionamide (73). Yield
92%, white solid, mp ) 61–63 °C, [R] ) -3.18 (c 1.0, CHCl3);
1H NMR (CDCl3) δ 7.59 (d, 1 H, J ) 8.4 Hz, H-5), 7.41 (d, 1 H,
J ) 2 Hz, H-2), 7.31 (d, 2 H, Ar), 7.22 (dd, 1 H, J ) 8.4, 2 Hz,
H-6), 7.07 (d, 2 H, Ar), 6.74 (bs, 1 H, NHSO2), 5.93 (bt, 1 H,
NHCO), 4.06 (dd, 1 H, J ) 4, 11.3 Hz, CH2OCO), 3.79 (dd, 1 H,
J ) 4.8, 11.3 Hz, CH2OCO), 3.41 (q, 1 H, J ) 7.1 Hz, CHCH3),
3.35 (ddd, 1 H, CH2NH), 2.95–3.05 (m, 4 H, CH2NH and SO2CH3),
2.55 (d, 2 H, J ) 7.5 Hz, CH2Ar), 2.09 (m, 1 H, CH), 1.46 (d, 3
H, J ) 7.1 Hz, CHCH3), 1.30 (s, 9 H, C(CH3)3), 1.22 (s, 9 H,
COC(CH3)3); IR (KBr) 3298, 2965, 1723, 1654, 1499, 1393, 1333,
1285, 1159, 1055 cm-1; MS (FAB) m/z 566 (MH+); Anal.
(C29H41ClN2O5S) C, H, N, S.
Molecular Modeling. The structure of compound 72 was built
using the Sybyl molecular modeling program (Tripos, Inc.), and
then the geometry was fully optimized using the Tripos force field
with the following nondefault options: (method) conjugate gradient;
(termination) gradient 0.01 kcal mol-1 Å-1; (max iterations) 10000.
The partial atomic charges were calculated by the Gasteiger-Hückel
method in the Sybyl program. The molecular surface maps color-
coded by lipophilic potential of the binding site of TRPV1 and
compound 72 were calculated using the MOLCAD program
implemented in Sybyl 6.9 prior to the docking study. The docking
study was conducted using the program DOCK implemented in
Sybyl 6.9. The initial receptor–ligand complex was determined
using graphical manipulations with continuous energy monitoring.
And then the obtained complex was fully optimized by energy
minimization using the Tripos force field. All computational work
was done on a Silicon Graphics O2 R10000 workstation.
1283, 1158 cm-1
;
MS (FAB) m/z 493 (MH+); Anal.
(C25H33FN2O5S) C, H, N, S.
N-[(2S)-2-(4-t-Butylbenzyl)-3-(pivaloyloxy)propyl]-(2R)-2-[3-
fluoro-4-(methylsulfonylamino)phenyl]propionamide (58). Yield
87%, white solid, mp ) 44–46 °C, [R] ) -8.1 (c 1.0, CHCl3); 1H
NMR (CDCl3) δ 7.51 (t, 1 H, J ) 8.25 Hz, H-5), 7.31 (d, 2 H,
Ar), 7.16 (dd, 1 H, J ) 11.2, 1.8 Hz, H-2), 7.03–7.1 (m, 3 H, Ar
and H-6), 6.41 (bs, 1 H, NHSO2), 5.91 (bt, 1 H, NHCO), 4.06 (dd,
1 H, J ) 4, 11.5 Hz, CH2OCO), 3.78 (dd, 1 H, J ) 5, 11.5 Hz,
CH2OCO), 3.43 (q, 1 H, J ) 7 Hz, CHCH3), 3.36 (ddd, 1 H,
CH2NH), 2.9–3.05 (m, 4 H, CH2NH and SO2CH3), 2.55 (d, 2 H, J
) 7.5 Hz, CH2Ar), 2.08 (m, 1 H, CH), 1.46 (d, 3 H, J ) 7 Hz,
CHCH3), 1.30 (s, 9 H, C(CH3)3), 1.22 (s, 9 H, COC(CH3)3); IR
(KBr) 3298, 2964, 1724, 1654, 1512, 1457, 1335, 1284, 1159 cm-1
;
MS (FAB) m/z 549 (MH+); Anal. (C29H41FN2O5S) C, H, N, S.
N-[(2S)-2-(4-t-Butylbenzyl)-3-(pivaloyloxy)propyl]-(2S)-2-[3-
fluoro-4-(methylsulfonylamino)phenyl]propionamide (59). Yield
92%, white solid, mp ) 43–45 °C, [R] ) +11.0 (c 1.0, CHCl3);
1H NMR (CDCl3) δ 7.52 (t, 1 H, J ) 8.25 Hz, H-5), 7.30 (d, 2 H,
Ar), 7.17 (dd, 1 H, J ) 11.2, 1.8 Hz, H-2), 7.0–7.1 (m, 3 H, Ar
and H-6), 6.50 (bs, 1 H, NHSO2), 5.90 (bt, 1 H, NHCO), 4.08 (dd,
1 H, J ) 4, 11.5 Hz, CH2OCO), 3.81 (dd, 1 H, J ) 5, 11.5 Hz,
CH2OCO), 3.45 (q, 1 H, J ) 7 Hz, CHCH3), 3.34 (ddd, 1 H,
CH2NH), 2.9–3.1 (m, 4 H, CH2NH and SO2CH3), 2.53 (ddd of
AB, 2 H, CH2Ar), 2.12 (m, 1 H, CH), 1.47 (d, 3 H, J ) 7 Hz,
CHCH3), 1.30 (s, 9 H, C(CH3)3), 1.22 (s, 9 H, COC(CH3)3); IR
Acknowledgment. I would like to thank Dr. Gavva for
providing the PDB file of the TRPV1 homology model. This
work was supported by Grant R01-2007-000-20052-0 from the
Basic Research Program of the Korea Science & Engineering
Foundation and by the Intramural Research Program of the NIH,
National Cancer Institute, Center for Cancer Research.
(KBr) 3299, 2963, 1724, 1653, 1512, 1457, 1335, 1284, 1159 cm-1
;
MS (FAB) m/z 549 (MH+); Anal. (C29H41FN2O5S) C, H, N, S.
N-[(2S)-2-(4-t-Butylbenzyl)-3-(pivaloyloxy)propyl]-(2S)-2-[3-
chloro-4-(methylsulfonylamino)phenyl]propionamide (60). Yield
90%, white solid, mp ) 55–57 °C, [R] ) +3.24 (c 1.0, CHCl3).
1H NMR (CDCl3) δ 7.61 (d, 1 H, J ) 8.4 Hz, H-5), 7.42 (d, 1 H,
J ) 2 Hz, H-2), 7.30 (d, 2 H, Ar), 7.23 (dd, 1 H, J ) 8.4, 2 Hz,
H-6), 7.05 (d, 2 H, Ar), 6.72 (bs, 1 H, NHSO2), 5.91 (bt, 1 H,
NHCO), 4.09 (dd, 1 H, J ) 4, 11.3 Hz, CH2OCO), 3.81 (dd, 1 H,
J ) 5, 11.3 Hz, CH2OCO), 3.43 (q, 1 H, J ) 7.1 Hz, CHCH3),
Supporting Information Available: Elemental analyses data
for final compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.

Stereospecific High-Affinity TRPV1 Antagonists
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 1 67
(VR1) antagonists: clinical answers await. Drug DiscoVery Today
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L. V.; Lundberg, D. J.; Blumberg, P. M. J. Med. Chem. 2003, 46,
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