Trisubstituted pyrimidines as transient receptor potential vanilloid 1 (TRPV1) antagonists with improved solubility

Article abstract of DOI:10.1016/j.bmcl.2007.09.080

A series of trisubstituted pyrimidines were synthesized to improve aqueous solubility of our first TRPV1 clinical candidate (1; AMG 517), while maintaining potent TRPV1 inhibitory activity. Structure-activity and structure-solubility studies led to the id

Full text of DOI:10.1016/j.bmcl.2007.09.080

Bioorganic & Medicinal Chemistry Letters 17 (2007) 6539–6545
Trisubstituted pyrimidines as transient receptor potential vanilloid
1 (TRPV1) antagonists with improved solubility
Xianghong Wang,a,* Partha P. Chakrabarti,a Vassil I. Ognyanov,a, Liping H. Pettus,a
Rami Tamir,b Helming Tan,a Phi Tang,a James J. S. Treanor,b
Narender R. Gavvab and Mark H. Normana
aDepartment of Chemistry Research & Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA
bDepartment of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA
Received 17 August 2007; revised 20 September 2007; accepted 24 September 2007
Available online 15 October 2007
Abstract—A series of trisubstituted pyrimidines were synthesized to improve aqueous solubility of our first TRPV1 clinical candidate
(1; AMG 517), while maintaining potent TRPV1 inhibitory activity. Structure–activity and structure–solubility studies led to the iden-
tification of compound 26. The aqueous solubility of 26 (P200 lg/mL, 0.01 HCl; 6.7 lg/mL, phosphate buffered saline (PBS); 150 lg/
mL, fasted-state simulated intestinal fluid (SIF)) was significantly improved over 1. In addition, compound 26 was found to be orally
bioavailable (rat Foral = 24%) and had potent TRPV1 antagonist activity (capsaicin IC50 = 1.5 nM) comparable to that of 1.
Ó 2007 Elsevier Ltd. All rights reserved.
Vanilloid receptor-1 (VR1 or TRPV1)1 is a membrane-
bound, non-selective ion channel with high permeability
for calcium2 and belongs to a super-family of ion chan-
nels known as the transient receptor potential channels
or TRPs.3 TRPV1 is activated or sensitized by several
stimuli including heat (>42 °C), protons (low pH),4
and ligands such as the endocannabinoid anandamide
TRPV1 clinical candidate, 1 (AMG 517, Fig. 1), a potent
and orally bioavailable TRPV1 antagonist (in vitro IC50
values <1 nM in both capsaicin- (CAP) and acid (pH 5)-
mediated assays13; rat Foral = 32%). In addition, com-
pound 1 was shown to be effective in a rodent ‘on-target’
biochemical challenge model (capsaicin-induced flinch)
and was anti-hyperalgesic in a model of inflammatory
pain (CFA-induced thermal hyperalgesia).12 However,
compound 1 suffered from low aqueous solubility which
presented challenges in its formulation development.
Therefore, our goal was to identify analogues of 1 that
had increased aqueous solubility while maintaining
TRPV1 potency. Previously we have reported one suc-
cessful approach toward this end that involved the
replacement of the 4-(trifluoromethyl)phenyl group of
compound 1 with various saturated aza-heterocycles.14
As an alternative approach to increasing aqueous solubil-
ity, we studied the effect of adding additional ionizable or
bulky substituents to the 2- or 5-positions of the pyrimi-
dine core (X or Y; compound 2, Fig. 1). In this paper,
we report the design, synthesis, and evaluation of this
series of trisubstituted pyrimidines. The structure–activ-
ity relationship (SAR) studies reported herein led to the
identification of potent TRPV1 antagonists with signifi-
cantly improved aqueous solubilities.
5
and lipoxygenase metabolites.6 TRPV1 is also acti-
vated by exogenous ligands such as the vanilloid capsa-
icin7 and resiniferatoxin (RTX).8 Recent studies have
demonstrated a reduction in thermal hyperalgesia in
acute- and sub-acute inflammatory pain models in mice
lacking the TRPV1 gene.9,10 These observations provide
evidence for the role of TRPV1 in the perception of pain
resulting from inflammation. Consequently, TRPV1
represents a novel target for the treatment of pain.
In our efforts toward the discovery of new analgesic
agents, we identified a series of 4,6-disubstituted pyrim-
idines as potent and selective TRPV1 antagonists.11,12
These studies culminated in the identification of our first
Keywords: Trisubstituted pyrimidines; Vanilloid receptor-1; Antago-
nists; Aqueous solubility.
*
Corresponding author. Tel.: +1 805 447 6923; fax: +1 805 480
1337; e-mail: qwang@amgen.com
Deceased.
For the evaluation of TRPV1 antagonist activity, we mea-
sured the inhibition of capsaicin (CAP)- and acid (pH 5)-
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.09.080

6540
X. Wang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6539–6545
NH
S
NH
CF3
CF3
O
O
N
N
X
Y
S
O
O
N
N
N
N
1
(AMG 517)
2
rTRPV1 (CAP): IC50 = 0.9 0.8 nM
rTRPV1 (pH 5): IC50 = 0.5 0.4 nM
Solubility
0.01 N HCl < 1.0 μg/mL
PBS
SIF
< 1.0 μg/mL
6.6 μg/mL
Figure 1. Lead compound 1 and generic substituted pyrimidine targets 2.
induced influx of 45Ca2+ into CHO cells expressing the rat
TRPV1. Functional activities [IC50 (nM)] are reported in
Tables 1–3. All compounds reported herein behaved as
antagonists.15 Results are reported as the average of at
least two independent experiments with three replicates
at each concentration ( SEM). To determine the aqueous
equilibrium solubility of these compounds, an automated
screening solubility assay in three media [0.01 N HCl,
phosphate-buffered saline (PBS, pH 7.4), and fasted-state
simulated intestinal fluid (SIF, pH 6.8)] was used.16 The
solubility range tested was 1–200 lg/mL.
acid 8. The TRPV1 assay results and aqueous solubility
data are reported in Table 1.
From this initial set of compounds we found that the
introduction of substituents at the 5-position of the
pyrimidine ring resulted in a significant decrease in
TRPV1 potency (7a–c; Table 1). In contrast, adding
substituents at the 2-position of pyrimidine was toler-
ated (7d–f; Table 1). Compound 7b showed a 270-fold
decrease in potency in the capsaicin-mediated assay
and 190-fold decrease in the pH-mediated assay. How-
ever, the 2-NH2substituted analogue 7e was only 12-fold
less potent than 1 in the capsaicin-mediated assay and
10-fold less potent in the pH-mediated assay. Further-
more, introduction of the bulkier NMe2 group at posi-
tion 5 of the pyrimidine (7c) resulted in an additional
loss of potency, relative to 7b, while the NMe2 group
at position 2 of the pyrimidine (7f) resulted in compara-
ble potency to 7e. As shown in Table 1, the small loss in
activity of 7d–f relative to1 was offset by some modest
improvements in aqueous solubility. These results sug-
gested that substituents may be tolerated at position 2
of the pyrimidine, but not at position 5.
Our strategy was to introduce ionizable groups to the
pyrimidine core of 1 to reduce the lipophilicity, or bulky
substituents to disrupt packing forces in the solid state.17
To determine the optimum placement for the additional
substituent, we began our SAR studies by first examin-
ing the effect of introducing small substituents at the
2- or 5-positions of the pyrimidine ring (e.g., Me,
NH2, and NMe2; compounds 7a–f, Table 1). The syn-
thetic methods used to prepare these trisubstituted pyr-
imidines are outlined in Scheme 1. Compounds 7a–f
were synthesized by the reaction of N-(4-hydrox-
ybenzo[d]thiazol-2-yl)acetamide 314 with 4-chloride of
pyrimidines 4a–f followed by Suzuki couplings with
commercially available 4-(trifluoromethyl)phenylboronic
With the 2-position of the pyrimidine ring identified as
the suitable position for substitution, we expanded our
Table 1. SAR and aqueous solubility: small substituents on the 2- and 5-positions of the pyrimidine core
NH
CF3
O
X
N
S
O
N
N
Y
Compound
X
Y
rTRPV1 IC50 (nM)
Solubility (lg/mL)
Capsaicin
pH
0.01 HCl
PBS
SIF
1
H
H
0.9 0.8
130 30
240 70
>4000
0.5 0.4
4
<1.0
61.0
8.6
<1.0
1.7
6.6
7a
7b
7c
7d
7e
7f
Me
NH2
NMe2
H
H
30
61.0
5.2
H
93 10
660 80
1.4 0.5
4.8 0.9
4.5 0.6
6.1
1.3
H
1.2
14
61.0
61.0
3.5
Me
NH2
NMe2
9.3
12
11
2
2.0
8.8
H
1
4.7
21
H
9
61.0
1.9

X. Wang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6539–6545
6541
Table 2. SAR and aqueous solubility: 2-substituted pyrimidines (directly-attached heterocycles)
NH
CF3
O
N
S
O
N
N
Y
Compound
Y
rTRPV1 IC50 (nM)
Solubility (lg/mL)
Capsaicin
pH
0.01 HCl
PBS
SIF
N
11a
11b
28
1
1.1 0.3
61.0
61.0
61.0
1.4
2.8
O
N
5.1 1.4
1.5 0.1
61.0
61.0
N
N
11c
11d
39
35
3
6
31
90
3
1
4.6
2.0
4.7
12
OH
21
OH
N
11e
11f
11g
410 90
6.2 0.2
1.8 0.2
27
1
61.0
15
6.0
3.4
31
19
COOH
N
1.1 0.3
0.6 0.1
61.0
5.2
61.0
N
Boc
12
13
910 600
190 20
8.4
52
1.7
5.5
120
72
N
H
3.2 0.8
0.4 0.1
N
14
100 50
100
4
75
8.9
180
67
N
N
11h
18
43 0.2
3.4 0.6
61.0
16
61.0
61.0
N
Boc
N
N
12
3
4.0 0.4
39

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X. Wang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6539–6545
Table 3. SAR and aqueous solubility: 2-substituted pyrimidines (aminomethyl-linked heterocycles)
NH
CF3
O
N
S
O
N
N
R
HN
Compound
R
rTRPV1 IC50 (nM)
Solubility (lg/mL)
Capsaicin
pH
11
0.01 HCl
PBS
SIF
190
19
6.1 0.7
2
1
P200
9.1
15
N
20
20
6
15
P200
P200
N
21
51 10
64 10
P200
160
9.4
P200
49
N
22
5.9 0.3
2.8 0.3
2.3
N
N
23
7.8
6.1
8.7
1
1
2
4.2
2
21
2.9
20
24
3.9 0.8
P200
P200
P200
61.0
7.2
5.0
62
N
25
9.3
1
N
N
2620
1.5 0.2
1.6 0.2
6.7
150
SAR by exploring larger substituents in this position.
The synthesis of compounds 11a–h and 22–26 is outlined
in Scheme 2. For these derivatives, the 2-position of the
pyrimidine was modified via late stage diversification of
intermediate 10 by either adding a primary or secondary
amine or by a Suzuki reaction with an appropriate boro-
nic acid. The required intermediate (10) was prepared by
a Suzuki coupling of 2,4,6-trichloropyrimidine (8) and 4-
(trifluoromethyl)phenylboronic acid (6) followed by an
aryl ether formation with N-(4-hydroxybenzo[d]thiazol-
2-yl)acetamide (3).18
In some cases additional modifications to the heterocy-
clic substituents were required to prepare the final target
compounds Schemes 3 and 4. For example, the Boc
group of tetrahydropyridine derivative 11g was removed
under acidic conditions to give the corresponding free
amine 12 (Scheme 3). The isobutyl derivative 13 was ob-
tained by reductive amination of compound 12 with iso-
butyraldehyde. Additionally, the double bond of 13 was
reduced by Pd(OH)2-catalyzed hydrogenation to give
the corresponding saturated piperidine analogue 14.
Similarly, the final isobutyl piperazine and piperidine

X. Wang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6539–6545
6543
NH
S
X
NH
S
O
O
N
X
Y
Cl
Cl
N
a
OH
O
Cl
+
N
N
N
N
Y
3
4a-f
5a-f
X
Y
H
H
H
a Me
b NH2
c NMe2
d H
Me
e H
H
NH2
NMe2
f
F3C
NH
CF3
O
X
N
B(OH)2
S
6
O
b
N
N
Y
7a-f
Scheme1. Reagentsand conditions:(a)K2CO3, DMF, 50 °C, 90%;(b) Pd(PPh3)2Cl2, Na2CO3, DME, EtOH, H2O, microwave, 120 °C, 10 min, 75–90%.
CF3
Cl
Cl
Cl
CF3
a
b
N
N
N
N
+
(HO)2B
Cl
Cl
N
6
8
9
NH
S
NH
S
CF3
CF3
c, d, or e
O
O
N
O
O
N
N
N
N
Y
Cl
10
11a-h, 15-17, 22-26
Scheme 2. Reagents and conditions: (a) Pd(OAc)2, PPh3, K2CO3, DME, 95 °C, 50%19; (b) 3, K2CO3, DMF, 50 °C, 90%; (c) 2 equiv amine, EtOH,
microwave, 140 °C, 30 min, 45–90%; (d) pyridin-4-ylboronic acid, Pd(PPh3)2Cl2, Na2CO3, DME, EtOH, H2O, microwave, 120 °C, 10 min, 85%; (e)
tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate, Pd(PPh3)4, Na2CO3, DME, H2O, 95 °C, 52%.
derivatives (18 and 19–21, respectively) were prepared
by deprotection of the Boc group followed by reductive
amination with isobutyraldehyde (Scheme 4).
er than 11b (21 lg/mL vs 61.0 lg/mL in 0.01 HCl). Di-
rect substitution of the pyrimidine core with a 4-
pyridinyl group provided more promising results. As
well as having improved solubility, compound 11f was
approximately equipotent to 11b in the capsaicin-medi-
ated assay and in acid-mediated assay. This result led
us to investigate the introduction of 4-pyridyl, 4-piperid-
inyl, 4-piperazinyl derivatives at the 2-position of the
pyrimidine in attempts to further enhance aqueous
solubility.
In the second phase of this investigation, we examined
the effect of the direct attachment of various heterocyclic
rings (e.g., morpholino, pyridinyl, and piperidine ana-
logues) to the 2-position of the pyrimidine core. As
shown in Table 2, the morpholino and piperidine ana-
logues 11a and b maintained good potency, but with
no improvement in aqueous solubility. Introduction of
polar substituents on the piperidine ring (11c–e) resulted
in much less potent TRPV1 antagonists, although some
improvements in solubility were observed. For example,
the 4-hydroxypiperidine analogue 11d was 7-fold less
potent than the piperidine derivative 11b in the capsai-
cin-mediated assay and 60-fold less potent in the acid-
mediated assay; however, the solubility of 11d was great-
Boc-protected tetrahydropyridine analogue 11g, initially
prepared as an intermediate, was quite potent with IC50
values of 1.8 and 0.6 nM in the CAP- and acid-mediated
assays, respectively (Table 2). Deprotection of the Boc
group was detrimental to activity (12); however, the po-
tency was restored with the N-alkylation of 12 with the
bulky isopropyl group. In this case, compound 13 re-

6544
X. Wang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6539–6545
NH
S
NH
CF3
CF3
O
O
N
N
S
O
O
N
N
N
N
c
N
N
R
11g: R = Boc
12: R = H
13: R = isobutyl
14
a
b
Scheme 3. Reagents and conditions: (a) 50% TFA/CH2Cl2, 98%; (b) NaBH(OAc)3, isobutyraldehyde, 1,2-dichloroethane, DMF, 74%; (c) Pd(OH)2,
HCO2NH4, butanol, 120 °C, 49%.
NH
NH
S
CF3
CF3
O
N
O
N
S
O
a, b
O
N
N
N
N
NH
NH
N
N
N
N
N
N
Boc
Boc
11h
15-17
18
19-21
Scheme 4. Reagents and conditions: (a) 50%TFA/CH2Cl2, 87%; (b) NaBH(OAc)3, isobutyraldehyde, 1,2-dichloroethane, DMF, 62%.
tained good TRPV1 potency and the solubility was sub-
stantially improved over compound 1. Unfortunately, a
significant decrease in potency was observed in both the
CAP- and acid-mediated assays with the reduction of
the double bond of compound 13 indicating that an
sp3 center attached to pyrimidine C2 was not well toler-
ated for this set of compounds (i.e., N-isobutyl piperi-
dine derivative 14).
maintained. Although the piperidine analogues with the
N-isopropyl at 3- or 4-positions showed reduced potency
(20 and 21), the derivative having N-isopropyl at 2-posi-
tion was more potent (19; IC50 = 6.1 nM in CAP-medi-
ated assay and IC50 = 11 nM in pH-mediated assay).
Given the success of aminomethyl-linked piperidine 19,
we prepared a series of aminomethyl-linked pyridine ana-
logues (i.e., 22–26). These derivatives were synthesized
according to the methods described in Scheme 2, starting
with commercially available aminomethyl pyridines. All
of these compounds had TRPV1 potencies of <10 nM.
In addition, the introduction of an a-methyl substituent
as additional bulk improved the aqueous solubility (Table
3). For example, compound 26 also showed better solubil-
ity than 22 in automated solubility assay.
Based on these results, we investigated piperazine deriv-
atives that had a similar geometry at the pyrimidine C2
as 11g and 13. The trends in potencies observed for
piperazine derivatives 11h and 18 were similar to their
tetrahydropyridine counterparts, 11g and 13. For exam-
ple, compound 18 maintained good TRPV1 potency
(IC50 = 12.0 nM
in
CAP-mediated
assay
and
IC50 = 4.0 nM in pH-mediated assay), but the solubility
of this compound was <50 lg/mL (16 lg/mL, 0.01 N
HCl; 61.0 7 lg/mL, PBS; 39 lg/mL SIF, Table 2).
Based on their excellent potencies and enhanced solubil-
ities, compounds 13, 19, and 26 were selected for in vivo
pharmacokinetic (PK) studies with intravenous (iv) dos-
ing in Sprague–Dawley rats (Table 4). Unfortunately,
In the final phase of this investigation we examined the ef-
fect of projecting the pyrimidine 2 substituent out of the
plane of the central core with the use of an aminomethyl
linking group. The objective was to further destabilize
the solid state packing forces and to explore deeper into
the receptor pocket. We also incorporated basic amine
functionality to the aminomethyl-piperidine derivatives
(19–21) to improve solubility. All of these analogues
had improved aqueous solubility, suggesting the benefit
of the 2-aminomethyl linking group with respect to
solubility. Additionally, with the appropriate position
of isopropyl substituent, TRPV1 activity could be
Table 4. Mean pharmacokinetic parameters following intravenous
dose in Sprague–Dawley ratsa
Compound
AUC0ꢀ1
(ng h/mL)
CL
(mL/h/kg)
Vss
(mL/kg)
t1/2
(h)
13
19
26
258
351
743
4040
2860
1350
6380
8290
6440
2.0
2.6
5.5
aDosed at 1 mg/kg as a solution in DMSO. n = 2 animals per study.
Interanimal variability was less than or equal to 30%.

X. Wang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6539–6545
6545
8. Appendino, G.; Szallasi, A. Life Sci. 1997, 60, 681.
following iv administration of 1 mg/kg, both 13 and 19
showed high rates of clearance (CL = 4040 mL/h/kg and
CL = 2860 mL/h/kg, respectively). However, compound
9. Caterina, M. J.; Leffler, A.; Malmberg, A. B.; Martin, W.
J.; Trafton, J.; Petersen-Zeitz, K. R.; Koltzenburg, M.;
Basbaum, A. I.; Julius, D. Science 2000, 288, 306.
10. Davis, J. B.; Gray, J.; Gunthrope, M. J.; Hatcher, J. P.;
Davey, P. T.; Overend, P.; Harries, M. H.; Latcham, J.;
Clapham, C.; Atkinson, K.; Hughes, S. A.; Rance, K.;
Grau, E.; Harper, A. J.; Pugh, P. L.; Rogers, D. C.;
Bingham, S.; Randall, A.; Sheardown, S. A. Nature 2000,
405, 183.
11. Norman, M. H.; Fotsch, C.; Doherty, E. M.; Bo, Y.;
Chen, N.; Chakrabarti, P.; Gavva, N. R.; Nishimura, N.;
Nixey, T.; Ognyanov, V. I.; Rzasa, R.; Stec, M.; Sura-
paneni, S.; Tamir, R.; Viswanadhan, V.; Zhu, J.; Treanor,
J. J. S. J. Med. Chem. 2007, 50, 3497.
12. Doherty, E. M.; Bannon, A. W.; Bo, Y.; Chen, N.;
Dominguez, C.; Falsey, J.; Fotsch, C.; Gavva, N. R.;
Katon, J.; Nixey, T.; Ognyanov, V. I.; Pettus, L.; Rzasa,
R.; Stec, M.; Surapaneni, S.; Tamir, R.; Zhu, J.; Treanor,
J. J. S.; Norman, M. H. J. Med. Chem. 2007, 50, 3515.
13. For the assay condition, see Doherty, E. M.; Fotsch, C.;
Bo, Y.; Chakrabarti, P.; Chen, N.; Gavva, N.; Han, N.;
Kelly, M. G.; Kincaid, J.; Klionsky, L.; Liu, Q.; Ognya-
nov, V. I.; Tamir, R.; Wang, X.; Zhu, J.; Norman, M. H.;
Treanor, J. S. J. Med. Chem. 2005, 48, 71.
14. Wang, H. L.; Katon, J.; Balan, C.; Bannon, A. W.;
Bernard, C.; Doherty, E. M.; Dominguez, C.; Gavva, N.;
Gore, V.; Ma, V.; Nishimura, N.; Surapaneni, S.; Tang,
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26 demonstrated
a
modest rate of clearance
(CL = 1350 mL/h/kg), a high volume of distribution
((Vss) 6440 mL/kg), and an elimination half-life (t1/2) of
5.5 h.21 In addition, compound 26 was relatively well ab-
sorbed following oral administration of 5 mg/kg
(Cmax = 280 ng/mL, AUC0ꢀ1 = 899 ng h/mL) with a
Foral = 24%.
In summary, a series of trisubstituted pyrimidines were
designed, synthesized, and evaluated for TRPV1 antago-
nist activities to block the capsaicin- and acid (pH 5)-in-
duced uptake of 45Ca2+ in CHO cell expressing rat
TRPV1. An automated solubility screening assay was
used as a valuable tool for the optimization of physical
properties of this series. Structure–activity and struc-
ture–solubility studies led to the identification of com-
pound 26, which was among the most potent analogues
(rTRPV1 CAP IC50 = 1.5 nM) in this series. This com-
pound exhibited 24% oral bioavailability. Importantly,
aqueous solubility of 26(P200 lg/mL, 0.01 HCl; 6.7 lg/
mL, PBS; 150 lg/mL SIF) was substantially improved
over compound 1.
15. All compounds were tested in a separate assay for agonist
activity.
Acknowledgments
16. (a) Tan, H.; Semin, D.; Wacker, M.; Cheetham, J. JALA
2005, 10, 364; (b) An automated solubility screening assay
was developed based on Symyx Solubility System (Santa
Clara, CA). Requiring 1 mg of solid compound, this assay
was used to determine the equilibrium solubility in three
aqueous media on a 96-well plate by HPLC-UV, with a
throughput of up to 192 compounds a week. The reporting
solubility range was 1–200 lg/mL, appropriate for discov-
ery lead optimization. Based on the validation results
obtained on commercially available drugs and Amgen
research compounds, the relative standard deviation of
this assay was found to be less than 10% for the solubility
range 50–200 lg/mL and up to 50% for the solubility
range 1–50 lg/mL.
We thank our colleagues Dr. Sekhar Surapaneni, Dr.
Annette Bak, and their coworkers in the PKDM and
pharmaceutics departments; Maggie Reed for carrying
out solubility studies; Chris Wilde for carrying out
NMR spectroscopic studies to confirm the structure of
compound 10; Dr. John Allen and Dr. Chris Fotsch for
the thorough review of the manuscript. We also acknowl-
edge Dr. Randy Hungate, Dr. Jean-Claude Louis, and
Dr. Paul J. Reider for their support.
References and notes
17. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P.
J. Adv. Drug Deliv. Rev. 1997, 23, 3.
1. Vanilloid receptor-1 is referred to as TRPV1 in this report
according to the adopted nomenclature Montell, C.;
Birnbaumer, L.; Flockerzi, V.; Bindels, R. J.; Bruford,
E. A.; Caterina, M. J.; Clapham, D. E.; Harteneck, C.;
Heler, S.; Julius, D.; Kojima, I.; Mori, Y.; Penner, R.;
Prawitt, D.; Scharenberg, A. M.; Schultz, G.; Shimizu, N.;
Zhu, M. X. Mol. Cell 2002, 9, 229.
2. Caterina, M. J.; Schumacher, M. A.; Tominaga, M.; Rosen,
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18. 1D NOESY was used to confirm the structure of
compound 10. NOEs were observed between the pyrim-
idine H19 and benzothiazole H7/8
:
NH
CF3
H19
O
N
S
O
N
N
H8
H7
Cl
10
4. Tominaga, M.; Caterina, M. J.; Malmberg, A. B.; Rosen,
T. A.; Gilbert, H.; Skinner, K.; Raumann, B. E.;
Basbaum, A. I.; Julius, D. Neuron 1998, 21, 531.
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.
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20. Compound 26 was also active in the human TRPV1 assays
with IC50 values of 2.1 and 1.7 nM in the CAP- and acid-
mediated assays, respectively.
21. For comparison, the pharmacokinetic parameters for
compound
6. Hwang, S. W.; Cho, H.; Kwak, J.; Lee, S.-Y.; Kang, C.-J.;
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1
are as follows: CL = 190 mL/h/kg,
Vss = 1556 mL/kg, AUC0ꢀ1 = 5400 ng h/mL, t1/2 = 6.3 h,
Foral = 32%. For further details regarding the pharmaco-
kinetic profile of compound 1, see Ref. 12.