Tetrahydro-naphthols as orally available TRPV1 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2012.03.108

Starting from a naphthol-based lead series with low oral bioavailability, we have identified potent TRPV1 antagonists with oral bioavailability in rats. These compounds emerged from SAR studies aimed at replacing the lead's phenol structure whilst maintai

Full text of DOI:10.1016/j.bmcl.2012.03.108

Bioorganic & Medicinal Chemistry Letters 22 (2012) 3408–3411
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Tetrahydro-naphthols as orally available TRPV1 inhibitors
Klaus Urbahns a, , Takeshi Yura a, Jang B. Gupta a, Masaomi Tajimi a, Hiroshi Fujishima a,
⇑
Tsutomu Masuda a, Noriyuki Yamamoto a, Yuka Ikegami a, Makiko Marumo a, Kayo Yasoshima a,
Nagahiro Yoshida a, Toshiya Moriwaki a, David Madge b, Fiona Chan b, Muneto Mogi a
a Research Center Kyoto, Bayer Yakuhin, Ltd, Kizu, Soraku, Kyoto 619-0216, Japan
b Xention Limited, Iconix Park, London Road, Pampisford, Cambridge CB22 3EG, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
Starting from a naphthol-based lead series with low oral bioavailability, we have identified potent TRPV1
antagonists with oral bioavailability in rats. These compounds emerged from SAR studies aimed at
replacing the lead’s phenol structure whilst maintaining potency. Compound rac-6a is an orally available
TRPV1 antagonist with single-digit nanomolar activity. The enantiomers show a low eudismic ratio at the
receptor level.
Received 4 March 2012
Revised 29 March 2012
Accepted 30 March 2012
Available online 6 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Naphthols
Urinary incontinence
Oral bioavailability
TRPV1
Vanilloid receptor antagonist
The vanilloid receptor TRPV1 is a cation channel and plays a key
role in detecting noxious and painful stimuli such as capsaicin, acid
or heat. Orally available agents directed against this pharmacolog-
ical target are of interest as potential treatments against pain,
cough or urinary incontinence.1 In previous communications, we
described a series of naphthol-based inhibitors ( Fig. 1, A) with
activity in rat cystitis models after intravenous administration
(1). The study was focused on B/C-ring as well as urea modifica-
tions and didn’t furnish oral compounds, most likely due to the
presence of the phenol group, which is notorious for phase II
metabolism and low oral exposure.2
As earlier studies had demonstrated a good correlation between
rat and human TRPV1 SAR, we focused on determining IC50s of hu-
man TRPV1 only.
Given the multiple pharmacokinetic problems of our series, we
decided to determine plasma levels after oral administration of
1 mg/kg to Sprague–Dawley rats and use areas under the curve
(AUC’s) for most compounds as a surrogate for bioavailability
(Tables 2–5).
As ‘vanilloid’-like structures are common for many TRPV1 mod-
ulators, it was not surprising that the 7-position of the naphthol
hydroxyl group in 2a was of particular importance for biological
activity (Table 1).4 The 6- and 5-substituted 2b and 2c were one or-
der of magnitude less active, indicating their inability to form a
hydrogen bond with TRPV1. A fluoro substituent in 8-position
was fairly tolerated (2d) but the 7-hydroxyl group couldn’t be
We describe herein A-ring modifications of our lead in an at-
tempt to generate orally available, single-digit nanomolar TRPV1
antagonists suitable for hypothesis testing in animal models and
man.
Materials 2a–f, 3a, 3g–i, 4a–e, 5a–c and 5e–f were synthesized
by reacting commercially available amines with the appropriate
isocyanate without orthogonal protection. Synthesis of the ali-
phatic amine 5d required intermediate protection as a phthalimide
(Fig. 2). Tetralone IV was obtained by Birch reduction from I’s cor-
responding ethyl ether. It was used as a building block for reduc-
tive (rac-6a) or Wittig-type transformations (rac 6b/6c).3
Cl
O
O
C
N
HN
B
CF3
N
HN
H
H
HO
HO
Cl
A
Cl
A
1
⇑
Corresponding author at present address: Merck KGaA, Frankfurter Strasse 250,
64293 Darmstadt. Tel.: +49 615172 6283; fax: +49 6151 72 3129.
Figure 1. Structure of the naphthol-based TRPV-1 antagonist lead
optimized derivative 1.
A
and an
E-mail address: Klaus.Urbahns@merckgroup.com (K. Urbahns).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.03.108

K. Urbahns et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3408–3411
3409
Table 1
NH2
NH2
O
H
N
Structure/activity relationship of naphthol-based TRPV-1 antagonists. Probing the
position and acidity of the aromatic hydroxy group.
HO
NH2
R
N
Cl
O
O
IIa: R=Me
IIb: R=CH2Ph
III
NH
N
H
CF3
I
NH2
NH2
O
HO
Compound
Structure
h-TRPV1 IC50 (nM)
2.2
HO
rac-V
2a
IV
a)
d)
e)
3d
3e
b)
b)
i)
3a
IIa
3b
3c
I
c)
h)
2b
18
IIb
IV
f)
b)
3f
HO
rac-V
rac-6a
g)
III
5d
j)
rac-6b
rac-6c
2c
45
k)
OH
Figure 2. Synthesis of TRPV1 inhibitors. Reaction conditions: (a) 40% MeNH2 in
MeOH, 160 °C, sealed tube, 2d, 44%. (b) 4-Cl-3-CF3-C6H3NCO (1.1 equiv), DMSO,
50 °C, 16 h, 20–80%. (c) C6H5CH2NH2 (2 equiv), 180 °C, 2d, 81%. (d) NCS (1.2 equiv),
THF, 0 °C, 2 h, 17%. (e) Ac2O (2 equiv), pyridine, 50 °C, 3 h, 44%. (f) NEt3 (2 equiv),
MeSO2Cl (1.5 equiv), THF, 0 °C, then 16 h, rt, 41%. (g) (1) 4-Cl-3-CF3-C6H3NCO
(1.1 equiv), DMSO, 50 °C, 16 h, 64%. (2) N2H4 (5 equiv, aq), EtOH, reflux, 6 h, 42%. (h)
(1) (tBuOCO)2O (1 equiv), THF, 70 °C, 18 h, 79%. (2) Cs2CO3 (2 equiv), DMF, EtI
(1 equiv), 60 °C, 2 h, 68%. (3) Aq HCl (4 N), dioxane, rt, 2 h, 87%. (4) Li (3 equiv), t-
BuOH (3 equiv), THF/liquid NH3 (1:15), À78 °C, 76%. (5) Aq HCl (2 N), THF, 40 °C,
1 h, 78%. (i) NaBH4 (0.5 equiv), MeOH 0 °C, 1 h, 71%. (j) (1) Pyridine (1.5 equiv),
C6H5CH2OCOCl (1.2 equiv), THF, rt, 1 h, 71%. (2) LDA (2.2 equiv), THF À78 °C,
MeOCH2PPh2 (1.1 equiv), rt, 16 h, 16%. (3) Aq HCl (2 N), THF, rt, 2 h; then: NaBH4
(1 equiv), EtOH, 2 h, 68%. (4) H2 (1 atm), Pd/C (cat.), EtOH, rt, 16 h, 62%. (5) 4-Cl-3-
CF3-C6H3NCO, dioxane, 50 °C, 2 h, 58%. (k) (1) BnBr (1.1 eq), K2CO3 (1.5 equiv),
acetone, reflux, 16 h, 75%. (2) MeP(Ph)3I (2 equiv), NaOtBu (2.1 equiv), THF, 100 °C,
13 h, 28%. (3) 9-BBN (2 equiv), THF, rt, 8 h; then: aq NaOH (3 N), aq H2O2 (33%), rt
6 h, 14%. (4) H2 (1 atm), Pd/C, EtOAc, rt, 1 h, 82%. (5) 4-Cl-3-CF3-C6H3NCO
(1.1 equiv), THF, rt, 16 h, 61%.
F
HO
2d
9.1
O
2e
2f
84
HO
HO
130
IC50 values are medians of 3 dose response curves.
able distance from ring B we looked into aliphatic alcohols at
three different linker lengths (5a–c). A two carbon atom spacer
was optimal (5b), reflecting the importance of having the hydro-
xyl group at the 7-position of the naphthalene (2a). In analogy
to what we observed with the naphthalene series, replacement
of 5b’s hydroxyl group with an amine reduced activity (5d).
Moving the side chain by one position resulted in further loss
of activity (5e).
Despite its reduced potency as compared to 2a, 5b’s increased
oral exposure clearly indicated the importance of removing the
phenol group in our lead. We attributed the decreased potency of
5b to an entropic effect due to the flexibility of the ethylene alcohol
side chain. This was based on the observation that restricting the
conformational degrees of freedom by incorporating a methyl
group adjacent to the flexible side chain increased potency (5f).
We therefore decided to cyclise the ring and reestablish the A-ring,
albeit in a saturated form (Table 5).
Tetrahydro naphthol rac-6a was the first example of an A-ring
modified derivative combining the absence of a phenol group and
meeting our single-digit nanomolar potency requirement. Appar-
ently, the ring closure provided an entropic advantage combined
with the correct geometry of the key hydroxyl group. Whilst fur-
ther side chain elongation reduced activity (rac-6b), the conform-
ationally restricted compound was again more active than its
open chain congener (rac-6b vs 5a). We separated rac-6a into
its enantiomers via chiral HPLC and were surprised to find no sig-
nificant differences in potency (4.3 nM vs 3.8 nM). Given the sub-
tle SAR trends described above, we found this low eudismic ratio
remarkable as replacing the alcohol with a methyl group resulted
replaced by an even more acidic carboxylic acid (2e). Shifting 2a’s
urea moiety into 2-position, resulted in 100-fold reduced activity
(2f).
Replacing the acidic hydroxyl group with basic amino groups
retained receptor affinity, but the naphthalene amines 3a and 3b
still suffered from low oral exposure (Table 2). A larger amino sub-
stituent decreased activity further (3c) and an additional substitu-
ent in the 6-position was not at all tolerated (3d).
The acetylated derivative 3e was of particular interest as it dis-
played an increase in oral exposure and attempts were made to
fine-tune the pKa to improve potency. Unfortunately, the sulphone
amides 3f–i were virtually inactive, despite displaying an NH
group with acidity similar to the original phenol at different linker
lengths. We assume that the steric demand of the sulphonyl group
is in conflict with optimal ligand/receptor interaction.
In another attempt to improve oral exposure we investigated
the heterocyclic compounds 4a–e (Table 3). Despite respectable
plasma levels (4a, 4c) the compounds didn’t meet our potency
benchmark of single-digit nanomolar activity. Moreover, in con-
trast to the naphthol series (2a–c), the position of the heterocyclic
NH group does not seem to play a role, suggesting that this moiety
is too remote to interact with the TRPV1 receptor.
As the naphthol ring A (Fig. 1, A) was believed to be the main
cause of the pharmacokinetic problems, we started to design
compounds in which this ring system was abandoned altogether
(Table 4). In order to present a hydrogen bond donor at a suit-

3410
K. Urbahns et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3408–3411
Table 3
Table 2
Structure/activity relationship of heterocyclic TRPV-1 antagonists
Structure/activity relationship of amine and sulphonamide TRPV-1 antagonists
Cl
O
Cl
O
NH
N
H
CF3
NH
N
H
CF3
Compound
Structure
h-TRPV1 IC50 (nM)
67
AUC (ng h/ml)
176
Compound
Structure
h-TRPV1 IC50 (nM)
34
AUC (ng h/ml)
217
H
N
4a
H2N
3a
H
N
4b
4c
180
33
n.d.
530
H
N
N
N
3b
3c
30
125
12
H
Ph
N
140
N
H
H
N
H2N
Cl
4d
4e
32
58
n.d.
n.d.
3d
>1000
n.d.
F3C
N
H
N
H
N
3e
3f
530
1591
709
n.d.
n.d.
n.d.
N
O
S
IC50 values are medians of 3 dose response curves. The area under the curve (AUC)
relates to plasma levels obtained after oral administration to rats at 1 mg/kg.
H
N
>1000
710
O O
Table 4
Structure/activity relationship of TRPV-1 antagonists. Effects of opening the A-ring
O O
S
3g
3h
3i
Cl
H2N
O
NH
N
H
CF3
H2N
460
S
O O
Compound
Structure
h-TRPV1 IC50 (nM)
220
AUC (ng h/ml)
n.d.
O O
S
>1000
H2N
5a
HO
IC50 values are medians of 3 dose response curves. The area under the curve (AUC)
relates to plasma levels obtained after oral administration to rats at 1 mg/kg.
HO
5b
5c
5d
56
374
n.d.
n.d.
330
in a 30-fold potency reduction (rac-6c), reemphasizing the impor-
tance of a hydrogen bond donor in this position. Apparently, the
conformational flexibility of the cyclohexene substructure allows
for accommodating both enantiomers into TRPV1.5
HO
H2N
>1000
The series as a whole remains lipophilic and compared to the
napthol fragment the tetrahydro naphthalene moiety confers only
slightly reduced octanol/water partition coefficients. (clogP 4.7 for
rac-6a vs clogP of 5.5 for 2a). However, to our delight, rac-6a
showed excellent exposure after oral administration, good oral bio-
availability in rats (F = 74%, 1 mg/kg oral dose, 0.1 mg/kg iv) and
acceptable free fraction in rat plasma (fu = 0.28%).
In summary, starting from a weak lead A with high clearance,
we have generated a single-digit nanomolar TRPV1 antagonist with
oral bioavailability in rats. Molecules like rac-6a were deemed suit-
able for further progression and their pharmacological properties
in vivo will be reported shortly.
5e
5f
230
16
75
HO
HO
n.d.
IC50 values are medians of 3 dose response curves. The area under the curve (AUC)
relates to plasma levels obtained after oral administration to rats at 1 mg/kg.

K. Urbahns et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3408–3411
3411
Table 5
WO 00/029577, 2000; Chem. Abstr. 2000, 133, 351661.; (k) Use of TRPV1
antagonists for UI: Shiroo, M.; Yura, T.; Yamamoto, N.; Tajimi, M.; Tsukimi, Y.
(Bayer Yakuhin), WO 04028440, 2004, Chem. Abstr. 2004, 140, 297515.;
Capsazepine’s activity in UI: (l) Bevan, S.; Hothi, S.; James, I. F.; Rang, H. P.;
Shah, K.; Walpole, C. S. J.; Teats, J. C. Br. J. Pharmacol. 1992, 107, 544; (m)
Walpole, C. S.; Bevan, S.; Boverman, G.; Boelsterli, J. J.; Breckenridge, R.; Davies, J.
W.; Hughes, G. A.; James, I.; Oberer, L. J. Med. Chem. 1942, 1994, 37; (n) Shaban,
A.; Drake, M.; Hashim, H. Autonom. Neurosci. 2010, 152, 4; (o) Sorbera, L. A.;
Bozzo, J.; Rosa, E.; Dulsat, C. Drugs of the Future 2008, 33, 455; (p) Tiwar, A.;
Naruhanahalli, K. S. Exp. Opin. Invest. Drugs 2006, 1017, 15; (q) Chancellor, M. B.;
de Groat, W. C. J. Urology 1999, 162, 3.
Structure/activity relationship of TRPV-1 antagonists. Discovery of tetrahydro naph-
thalene derivatives.
Cl
O
NH
N
H
CF3
2. Urbahns, K.; Yura, T.; Mogi, M.; Tajimi, M.; Fujishima, H.; Masuda, T.; Yoshida,
N.; Moriwaki, T.; Madge, D.; Chan, F.; Gupta, J. B. Bioorg. Med. Chem. Lett. 2011,
21, 3354.
Compound
Structure
h-TRPV1 IC50 (nM)
3.3
AUC (ng h/ml)
650
3. (a) Synthetic details: Bouchon, A. Diedrichs, N.; Hermann, A.; Lustig, K.; Meier, H.
Pernerstorfer, J.; Reissmueller, E.; DeVry, J.; Mogi, M.; Urbahns, K.; Yura, T.;
Fujishima, H.; Tajimi, M.; Yamamoto, N.; Yuasa, H.; Gupta, J.B.; Tsukimi, Y.;
Hayashi, F. (Bayer Yakuhin) WO 2005040119, 2005; Chem. Abstr. 2005, 142,
447019.; (b) Bouchon, A. Diedrichs, N.; Hermann, A.; Lustig, K.; Meier, H.
Pernerstorfer, J.; Reissmueller, E.; Mogi, M.; Yura, T.; Fujishima, H.; Seki, M.;
Koriyama, Y.; Yasoshima, K.; Misawa, K.; Tajimi, M.; Yamamoto, N.; Urbahns, K.;
Hayashi, F.; Tsukimi, Y.; Gupta, J.B. (Bayer Yakuhin) WO2005040100, 2005;
Chem. Abstr. 2005, 142, 447018.; (c) Yura, T.; Mogi, M.; Ikegami, Y.; Masuda, T.;
Kokubo, T.; Urbahns, K.; Lowinger, T. B.; Yoshida, N.; Freitag, J.; Meier, H.;
Wittka-Nopper, R.; Marumo, M.; Shiroo, M.; Tajimi, M.; Takeshita, K.; Moriwaki,
T.; Tsukimi, Y. (Bayer Yakuhin) WO 03014064 2003; Chem. Abstr. 2003, 139
79169.; (d) Compound rac-6a: 1H NMR (DMSO-d6): d 1.57–1.58 (m, 1H), 1.87–
1.90 (m, 1H), 2.36–2.42 (m, 1H), 2.63–2,76 (m, 1H) 2.83–2.87 (m, 2H), 3.91–3.96
HO
rac-6a
rac-6b
rac-6c
87
93
n.d.
n.d.
HO
(m,1H), 4.87 (d, J = 4.1 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 7.06 (
7.58 (d, J = 7.6 Hz, 1H), 7.61–7.62 (m, 2H), 7.93 (s, 1H), 8.09 (s, 1 H), 9.47 (s, 1H).
Mp (AcOEt/n-hexane 1/2): 227–228 °C.
W
t, J ꢀ7.6 Hz, 1H),
IC50 values are medians of 3 dose response curves. The area under the curve (AUC)
relates to plasma levels after oral administration to rats at 1 mg/kg.
4. Assay descriptions: h-VR1 c-DNA was transfected into a CHOluc9aeq cell line
(pcDNA3) containing aequorin and CRE-luciferase reporter genes. After loading
with Fluo-3AM (2 lM, Molecular Probes) and stimulation with capsaicin
(10 nM), fluorescence changes were recorded for 1 min (kex = 488 nm/
kem = 540 nm, Hamamatsu photonics) and IC50 values determined.
References and notes
5. As both enantiomers have similar affinity to TRPV1, we would like to suggest
that 6a and ent-6a bind to TRPV1 with their hydroxyl groups in pseudo
equatorial position of the cyclohexene conformation as indicated below. The
alternative pseudo axial position is energetically less favorable and the hydroxyl
groups would point towards dissimilar trajectories.
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