Chain branching approach in structure modification of TRPV1 receptor antagonist MK056 and its analogs

Article abstract of DOI:10.1007/s12272-012-0212-x

A series of chain branched 1,3-dibenzylthiourea derivatives were designed, synthesized, and evaluated for their antagonist activity against TRPV1. The synthesized chain branched 1,3dibenzylthioureas 9a-g were tested for their antagonist activities against TRPV1 by ⁴⁵ Ca ²⁺ influx assay using neonatal rat cultured spinal sensory neurons. Fluorinated ethyl-branched analog 9g showed the most potent antagonist activity with an IC₅₀ value of 0.41 μM, but all of the chain branched analogs were less potent than the parent compounds MK-056 and SC0030, indicating that chain branching on the benzylic position of B-ring is detrimental to potency. Optimized receptor binding seems to be interfered by chain branching, and resulted in decrease in potency.

Full text of DOI:10.1007/s12272-012-0212-x

Arch Pharm Res Vol 35, No 2, 321-326, 2012
DOI 10.1007/s12272-012-0212-x
Chain Branching Approach in Structure Modification of TRPV1
Receptor Antagonist MK056 and its Analogs
Mijung Jang1, Chong Hyun Ryu1,Young-Ho Park2, and Hee-Doo Kim1
2
1College of Pharmacy, Sookmyung Women’s University, Seoul 141-742, Korea and AmorePacific R & D Center, Youngin
449-900, Korea
(Received October 27, 2011/Accepted November 6, 2011)
A series of chain branched 1,3-dibenzylthiourea derivatives were designed, synthesized, and
evaluated for their antagonist activity against TRPV1. The synthesized chain branched 1,3-
dibenzylthioureas 9a
influx assay using neonatal rat cultured spinal sensory neurons. Fluorinated ethyl-branched
analog 9g showed the most potent antagonist activity with an IC50 value of 0.41 M, but all of
-g
were tested for their antagonist activities against TRPV1 by 45Ca2+-
µ
the chain branched analogs were less potent than the parent compounds MK-056 and SC-
0030, indicating that chain branching on the benzylic position of B-ring is detrimental to
potency. Optimized receptor binding seems to be interfered by chain branching, and resulted
in decrease in potency.
Key words: Chain branching, TRPV1, 1,3-Dibenzylthioureas, Antagonist, 45Ca2+-influx assay
from the known agonist structure of a receptor. In this
sense, chain branching could be a promising method
INTRODUCTION
Chain branching is one of the molecular modifica- for this important pharmacological change (Yoon et
tion method used in drug design and lead develop- al., 2003). In addition, chain branching can lead to
ment (Silverman, 2004). However, as a result of larger marked alterations in the physicochemical and bio-
molar volumes and shapes of branched compounds, logical properties of chain branched analogues. Thus,
chain branching usually will lower the potency of a the introduction of a branched chain into biologically
compound. When lipophilicity is among the important prevalidated drug scaffolds represents an important
parameters for potency of a drug or lead, a branched way of drug design.
alkyl chain is less lipophilic than the corresponding
On the other hand, TRPV1 is a ligand-gated non-
straight alkyl chain. Optimized receptor binding inter- selective cation channel vanilloid receptor 1 (VR1)
action might also be interfered by chain branching. with high Ca2+ permeability (Szallasi et al., 2007),
For these reasons, chain branching was not frequently emerging as a novel target for the treatment of pain
used as expected, compared to other molecular modifi- with entirely different mechanism from the previously
cation methods. Nonetheless, newly created stereo- known (Westaway, 2007). Based on the premise that
genic centers by chain branching can alter both the direct blockage of TRPV1 by its antagonists could be a
binding mode and the selectivity to a receptor or an promising way to shut down the pathway involved in
enzyme, ultimately resulting in a major pharmacolo- nociception (Rami and Gunthorpe, 2004), extensive
gical change. As ever increasing importance of receptor works have been done to develop new TRPV1 antag-
as drug target, it is often required a molecular modifi- onists during the past decade (Gunthorpe and Chizh,
cation method that could invoke receptor antagonism 2009; Khairatkar-Joshi and Szallasi, 2009; Kym et al.,
2009; Lambert, 2009). We have also reported the
dibenzylthiourea analogs including MK-056 (
1) (Park
Correspondence to: Hee-Doo Kim, College of Pharmacy, Sook-
myung Women’s University, Seoul 140-742, Korea
Tel: 82-2-710-9567, Fax: 82-2-703-0736
et al., 2004), and SC-0030 ( ) (Suh et al., 2003), which
exhibit highly potent competitive TRPV1 antagonist
effects. Based on chain branching approach mentioned
2
E-mail: hdkim@sm.ac.kr
321

322
M. Jang et al.
Fig. 1. Chemical structure of 1,3-dibenzylthioureas
previously, we also designed and synthesized methyl
(
R
)-
(6a)
AlCl3 (815 mg, 6.11 mmol) was added portionwisely
ity compared with parent compound MK-056. This to a stirred mixture of ( )- -(1-phenylethyl)formamide
chain branching has become a key element to design- 5a, 456 mg, 3.05 mmol) and -butyl chloride (664 L,
ing novel TRPV1 antagonists having dibenzylthiourea 6.11 mmol) in anhydrous dichloroethane (10 mL) at
scaffold. Encouraged with the result shown by ATC-
40oC. The mixture was stirred for 90 min at 40oC,
N
-(1-(4-(tert-butyl)phenyl)ethyl)formamide
branched ATC-120 (3) (Ryu et al., 2004) as TRPV1 an-
tagonist, showing 2-fold more potent antagonist activ-
R
N
(
t
µ
−
−
120, we try to introduce a stereogenic center at another then quenched by addition of finely crushed ice and
benzylic position in MK-056 and SC-0030, as shown in 10% hydrochloric acid. The layers were separated, and
Fig. 1.
the aqueous layer was extracted twice with dichloro-
methane (20 mL). The combined organic layers were
neutralized with aq. NaHCO3 solution, washed with
water and brine, dried over anhydrous Na2SO4, and
MATERIALS AND METHODS
The melting points were obtained using Büchi 535 concentrated in vacuo. The residue was purified by
melting point apparatus and were uncorrected. Opti- column chromatography (silica gel; 33% ethyl acetate
cal rotations were measured on a JASCO DIP 1000 in
n
-hexane) to afford the title compound 6a as a solid
digital polarimeter. H-NMR and 13C-NMR spectra (194.5 mg, 31%). m.p. 81-83oC; [α D24 +135 (
0.5, CHCl3);
were obtained on a Varian Inova 400 spectrometer 1H-NMR (400 MHz, CDCl3)
8.09 (s, 1H), 7.30 (d, 2H,
and the chemical shifts are reported as values in parts = 8.2 Hz), 7.19 (d, 2H, = 8.2 Hz), 5.75 (bs, 1H), 5.14
= 7.2 Hz), 1.45 (d, 3H, = 6.8 Hz), 1.24 (s,
1
]
c
δ
J
J
per million (
δ
) relative to tetramethylsilane (TMS) as (quint,
J
J
an internal standard. The infrared spectra (IR) were 3H); IR (KBr) cm−1 3326, 2959, 1663, 1460, 1382.
recorded on a JASCO FT/IR-430 spectrophotometer.
Thin layer chromatography (TLC) was carried out on
0.25 mm E. Merck precoated silica gel glass plates
(60F254). Column chromatography was performed using
(
S)
(6b)
By the same procedure as described for the prepara-
-N-(1-(4-(tert-butyl)phenyl)ethyl)formamide
the forced flow of indicated solvent on Merck Kieselgel tion of compound 6a, title compound 6b was obtained
60 (230-400 mesh). Chiral HPLC was performed using from ( )- -(1-phenylethyl)formamide (5b) as solid in
a Shimadzu LC-10AS pumping system and Shimadzu 60% yield. Analytical data are identical with those of
S
N
25
SPD-10A UV detector with a chiral column (Chiralcel 6a except optical rotation value. [α D
]
−132 (c 0.9,
OD, 0.46 cm ( 25 cm, Daicel Chemical Ind., Ltd). CHCl3).
Φ) ×
Unless otherwise noted, the materials were obtained
from commercially available sources and were used
without further purification. THF was freshly distilled
from sodium benzophenone ketyl under an argon
(
R N-(1-(4-(tert-butyl)phenyl)propyl)formamide
)-
(6c)
By the same procedure as described for the prepara-
atmosphere. Benzene, DCM, DMF, triethylamine (TEA) tion of compound 6a, title compound 6c was obtained
and toluene were freshly distilled under a nitrogen from ( )- -(1-phenylpropyl)formamide (5c) as liquid
atmosphere with calcium hydride. in 59% yield. [
MHz, CDCl3)
4H), 5.76 (bs, 1H), 4.90 (quint, 1H,
S
N
24
α
]
+116 (
c
0.5, CHCl3); 1H-NMR (400
= 6.4 Hz), 7.32-6.97 (m,
= 7.6 Hz), 1.83-
D
δ
8.13 (d, 1H, J
J

Chain Branched 1,3-Dibenzylthioureas as TRPV1 Receptor Antagonists
323
1.75 (m, 2H), 1.24 (s, 9H), 0.85 (t, 3H,
(NaCl, neat) cm−1 3277, 2964, 1658, 1460, 1382.
J
= 7.2 Hz); IR (KBr) cm−1 3350, 3259, 3063, 3027, 2975, 2928, 1545,
1511; HRMS (FAB+) calcd for C17H22N3O2S2 (M+H)
364.1153, found 364.1157.
(
R
)-1-(4-(tert-butyl)phenyl)ethanamine (7a)
To a solution of ( )- -(1-(4-(tert-butyl)phenyl)ethyl)
R
N
(S)-N-(4-((3-(1-phenylethyl)thioureido)methyl)
formamide (6a, 50 mg, 0.244 mmol) in ethanol (5 mL)
phenyl)methanesulfonamide (9b)
was added 1N aqueous KOH solution (1 mL) at room
By the same procedure described above, the product
temperature. The reaction mixture was concentrated was obtained from 8a and (S)-(-)-α-4-methylbenzyl-
in vacuo, and then diluted with dichloromethane (30 amine (4b) as solid in 52% yield. Analytical data are
mL). The organic layer was washed with water and identical with those of 9a except optical rotation
brine, dried over anhydrous Na2SO4, and concentrated value. [α D
] c 0.7, CHCl3).
20 +35.1 (
in vacuo to afford the title compound 7a as liquid (37
25
mg, 86%). [α D
]
+10.7 (
c
0.8, CHCl3); 1H-NMR (400
= 8.2 Hz), 7.20 (d, 2H,
(R)-N-(4-((3-(1-(4-(tert-butyl)phenyl)ethyl)thio-
ureido)methyl)phenyl)methanesulfonamide (9c)
By the same procedure described above, the product
MHz, CDCl3)
δ
7.29 (d, 2H,
J
J
= 8.2 Hz), 4.08 (br s, 2H), 1.24 (s, 9H); IR (NaCl, neat)
cm−1 3356, 3285, 1578, 1460, 1363.
was obtained from 8a and 7a as solid in 62% yield.
20
m.p. 88-90oC; [
α]
−17.0 (c
0.5, CHCl3); 1H-NMR (400
D
MHz, CDCl3): 7.35 (d, 2H,
By the same procedure as described for the prepara- 8 Hz), 7.07 (d, 2H, = 8.4 Hz), 7.00 (s, 1H), 6.96 (d,
tion of compound 7a, title compound 7b was obtained 2H, = 8.4 Hz), 6.52 (s, 1H), 5.75 (s, 1H), 4.7 (dd, 2H,
from ( )- -(1-(4-(tert-butyl)phenyl)ethyl)formamide = 14.8 Hz, 4.8 Hz), 4.58 (dd, 1H, = 14.8 Hz, 4.8
= 6.8 Hz), 1.3 (s, 3H);
J = 8.0 Hz), 7.23 (d, 2H, J =
(S)-1-(4-(tert-butyl)phenyl)ethanamine (7b)
J
J
S
N
J
J
(
6b) as liquid in 90% yield. Analytical data are iden- Hz), 2.98 (s, 3H), 1.52 (d, 3H, J
tical with those of 7a except optical rotation value. IR (KBr) cm−1 3350, 3260, 3025, 2964, 1614, 1326,
[
α D
]
−
11.0 (
c
1.0, CHCl3).
1152; HRMS (FAB+) calcd for C21H30 N3O2S2 (M+H)
420.1779, found 420.1775.
25
(
R
)-1-(4-(tert-butyl)phenyl)propan-1-amine (7c)
By the same procedure as described for the prepara-
(S)-N-(4-((3-(1-(4-(tert-butyl)phenyl)ethyl)thio-
tion of compound 7a, title compound 7c was obtained
ureido)methyl)phenyl)methanesulfonamide (9d)
from (R)-N-(1-(4-(tert-butyl)phenyl)propyl)formamide
By the same procedure described above, the product
25
(
6c) as liquid in 28% yield. [
α
]
+6.94 (
c
0.5, CHCl3); was obtained from 8a and 7b as solid in 62% yield.
D
1H-NMR (400 MHz, CDCl3)
δ
7.29-7.17 (m, 4H), 4.07- Analytical data are identical with those of 9c except
3.83 (m, 1H), 1.73 (s, 2H), 1.25 (s, 9H), 0.79 (s, 3H); IR optical rotation value. [
α] c 1.0, CHCl3).
20 +16.5 (
D
(NaCl, neat) cm−1 3315, 2963, 1556, 1460, 1363.
(R)-N-(4-((3-(1-(4-(tert-butyl)phenyl)propyl)thio-
(R
)-
phenyl)methanesulfonamide (9a)
To a solution of the
methanesulfonamide (8a, 40.0 mg, 0.17 mmol) in di-
chloromethane (5 mL) was added ( )-( )- -4-methyl- 7.29-6.98 (m, 8H), 6.83 (s, 1H), 6.63 (s, 1H), 5.71 (s,
benzylamine (4a, 23.0 mg, 0.20 mmol) at room tem- 1H), 4.67 (dt, 1H, = 14.2 Hz, 6.0 Hz), 4.45 (dt, 2H,
perature. After being stirred for 12 h at room temper- 12.6 Hz, 4.4 Hz), 2.90 (s, 3H), 1.86-1.66 (m, 2H), 1.24 (s,
N
-(4-((3-(1-phenylethyl)thioureido)methyl)
ureido)methyl)phenyl)methanesulfonamide (9e)
By the same procedure described above, the product
N
-(4-isothiocyanatomethylphenyl) was obtained from 8a and 7c as syrup in 34% yield.
20
[α]D −24.34 (c
0.71, CHCl3); 1H-NMR (400 MHz, CDCl3):
R
− α
J
J =
ature, the reaction mixture was quenched with H2O (1 9H), 0.83 (dt, 3H,
J = 7.2 Hz, 2.0 Hz); IR (NaCl, neat)
mL) and diluted with dichloromethane (30 mL). The cm−1 3259, 1547, 1512, 1328, 1152; HRMS (FAB+) calcd
organic layer was washed with brine, dried over anhy- for C22H32 N3O2S2 (M+H) 434.1936, found 434.1936.
drous Na2SO4, and concentrated in vacuo. The residue
was purified by column chromatography (silica gel;
33% ethyl acetate in -hexane) to afford the title com-
pound 9a as solid (33.0 mg, 46%). m.p. 69-71oC; [
33.14 (
0.53, CHCl3); 1H-NMR (400 MHz, CD3OD)
7.61 (s, 1H), 7.30-7.24 (m, 5H), 7.03 (d, 2H,
Hz), 6.92 (d, 2H,
= 8.0 Hz), 6.74 (s, 1H), 5.96 (s, 1H), m.p. 70-72oC; [α D
4.83 (s, 2H), 4.64 (d, 1H, = 15.2 Hz), 4.49 (d, 1H, MHz, CDCl3): 7.30 (s, 1H), 7.26 (d, 2H,
15.2 Hz), 2.92 (s, 3H), 1.47 (d, 3H, = 6.8 Hz); IR 7.15 (d, 2H, = 8.4 Hz), 6.88 (s, 2H), 5.24 (s, 1H), 4.74
(R)-N-(4-((3-(1-(4-(tert-butyl)phenyl)ethyl)thio-
ureido)methyl)-2-fluorophenyl)methanesul-
fonamide) (9f)
n
20
α
]
D
−
c
δ
By the same procedure described above, the product
J
= 8.0 was obtained from 8b and 7a as solid in 19% yield.
22
J
]
−
40.56 (
c
0.1, CHCl3); 1H-NMR (400
= 8.4 Hz),
J
J
=
δ
J
J
J

324
M. Jang et al.
(d, 1H,
3H), 1.38 (d, 3H,
J
= 12.4 Hz), 4.51 (d, 1H,
J
= 12.4 Hz), 2.83 (s,
µ
Ci/mL 45Ca2+ and 0.5 M capsaicin together with the
J = 6.8 Hz), 1.21 (s, 9H); IR (KBr) test concentration of the compound was added to each
cm−1 3354, 3259, 3069, 2963, 2926, 1590, 1547, 1510, well. The neurons were incubated at room tempera-
1332, 1157; HRMS (FAB+) calcd for C21H29 N3O2S2 ture for 10 min, and then the Terasaki plates were
(M+H) 438.1685, found 438.1687.
)- -(4-((3-(1-(4-(tert-butyl)phenyl)propyl)
thioureido)methyl)-2-fluorophenyl)methane
sulfonamide) (9g)
washed six times in HEPES (10 mM, pH 7.4)-buffered
calcium- and magnesium-free Hank's balanced salt
solution and dried in an oven. Sodium dodecyl sulfate
(
R N
(0.3%, 10
µL) was then added to dissolve the cells and
extract the 45Ca2+. The contents of each well were
By the same procedure described above, the product transferred to scintillation vials and counted in 3 mL
was obtained from 8b and 7c as solid in 39% yield. of aquasol-2 scintillant. Antagonistic activities of test
0.6, CHCl3); 1H-NMR (400 MHz, CDCl3): compounds were given as IC50 (the concentration of
25
[
δ
α D
]
−
37.7 (
c
7.30 (s, 1H), 7.26 (d, 2H,
= 8.4 Hz), 6.88 (s, 2H), 5.24 (s, 1H), 4.74 (d, 1H,
12.4 Hz), 4.51 (d, 1H,
(d, 3H, = 6.8 Hz), 1.21 (s, 9H); 7.39-6.66 (m, 7H), compound was tested at least in two independent
6.61 (s, 1H), 5.74 (s, 1H), 4.89- 4.80 (m, 1H), 4.49 (dt, experiments.
2H, = 14.0 Hz, 4.8 Hz), 2.99 (s, 3H), 1.93-1.73 (m,
J
= 8.4 Hz), 7.15 (d, 2H,
J
the compound necessary to reduce the response to 0.5
J
=
µM capsaicin by 50%). The IC50 values were estimated
J
= 12.4 Hz), 2.83 (s, 3H), 1.38 at least three replicates at each concentrated. Each
J
J
2H), 1.30 (s, 9H), 0.92 (dt, 3H,
J = 7.0 Hz, 1.2 Hz); IR
RESULTS AND DISCUSSION
(KBr) cm−1 3257, 2963, 1547, 1512, 1332, 1157; HRMS
(FAB+) calcd for C22H31FN3O2S2 (M+H) 452.1842, found
452.1840.
MK-056 (1) and SC-0030 (2) were also chosen as
reference compounds in order to clarify the chain
branching effect. Because these compounds represent
the most important scaffolds in 1,3-dibenzylthioureas
Culture of DRG neurons
DRG neurons were prepared from neonatal Sprague- with high antagonist activity. Thus, target compounds
Dawley rats. DRGs of all spinal levels were dissected in this study were the methyl and ethyl branched
aseptically and collected. Ganglia were incubated se- derivatives of MK-056 (1) and SC-0030 (2). These
quentially for 30 min at 37oC in 200 U/mL collagenase targets were synthesized via the route outlined in
and 2.5 mg/mL trypsin. The digestion was halted by Scheme 1-2. Optically active methyl or ethyl branched
an addition of an equal volume of DME/F12 medium benzylamines 7a-c were synthesized via the route
supplemented with 10% horse serum. The ganglia were outlined in Scheme 1. Commercially available, optically
then triturated through a fire-polished Pasteur pipet, active α-methyl or α-ethylbenzylamines 4a-c were for-
filtered through nylon membrane, and spun down. mylated in the presence of HCOOH and Ac2O according
Dissociated cells were plated onto Terasaki plates pre- to the literature methods (Iwata and Kuzuhara, 1989).
viously coated with 10
density of 1500-1700 neurons/well. The cells were then tert-butyl chloride and AlCl3 under standard condition
cultured for 3 days in DME/F12 medium containing gave the corresponding tert-butylated product 6a in
1.2 g/L sodium bicarbonate, 15 mM HEPES, 50 mg/L moderate yields. Hydrolysis of formamides 6a with
gentamycin, and 10% horse serum, diluted 1:1 with KOH gave desired corresponding benzylamines 7a
µg/mL poly-D-ornithine at a Friedel-Crafts alkylation of formamides 5a-c using
-c
-c
-c
identical medium conditioned by C6 glioma cells (2 in good yields. The requisite isothiocyanates 8a and
days on a confluent monolayer) in a humidified atmos- 8b were prepared according to the previously reported
phere at 37oC containing 5% CO2. Medium was sup- method (Lee et al., 2003; Suh et al., 2005). Finally, 8a
plemented with 200 ng/mL nerve growth factor. Cyto- and 8b were treated with optically active
sine arabinoside (100 M) was added for the first 2 benzylamine 4a and 7a respectively in dry dichlo-
romethane to give the chain branched 1,3-dibenzyl-
thioureas 9a as target compounds.
The synthesized chain branched 1,3-dibenzylthio-
α-branched
µ
-c
-c
days to kill dividing nonneuronal cells.
-g
45Ca2+ Uptake assays
Terasaki plates containing DRG neurons grown for ureas 9a-g were tested for their antagonist activities
3 days were equilibrated with four washes of HEPES against TRPV1 by 45Ca2+-influx assay using neonatal
(10 mM, pH 7.4)-buffered calcium- and magnesium- rat cultured spinal sensory neurons (Wood et al., 1988).
free Hank's balanced salt solution. The solution in The results are summarized in Table I. MK-056 (
each well was removed from the individual wells. For and SC-0030 ( ) were used as reference compounds.
antagonistic studies, medium (10 L) containing 10 As shown in Table I, ( )-isomers are uniformly more
1)
2
µ
R

Chain Branched 1,3-Dibenzylthioureas as TRPV1 Receptor Antagonists
325
Scheme 1. Reagents and conditions: a) HCOOH, Ac2O, 96-97%; b) t-BuCl, AlCl3, ClCH2CH2Cl, 59%; c) KOH. EtOH, 86%
Scheme 2. Reagents and conditions: a) DCM, rt, 46-74%
Table I. 45Ca2+-Uptake inhibition by chain branched ana-
potent than (S)-isomers. When removing tert-butyl
logues
group on the phenyl ring, antagonist activities were
dropped drastically as shown by 9a and 9b. This result
is consistent the with the previous results that 4-posi-
tioned tert-butyl group on the B ring is very reluctant
to permit chemical modification (Li et al., 2009). Intro-
duction of branched methyl group on MK-056 (9c and
9d) dropped potency by a factor of 5 to 50-fold depend-
ing on their absolute configurations. Eutomer 9c with
45Ca2+ influx activity ( M)a
µ
Com-
pound
X
R1 R2
Y
Agonist
(EC50)
Antagonist
(IC50)
9a
9b
9c
9d
9e
H
H
H
H
H
F
F
H
F
Me
H
Me
H
Et
Me
Et
H
H
Me
H
Me
H
H
H
H
H
H
>100
>100
>100
>100
>100
>100
>100
>100
>100
8.90
>3000.
0.55
4.50
0.74
0.64
0.41
0.11
0.04
t
t
t
t
t
t
t
-Bu
-Bu
-Bu
-Bu
-Bu
-Bu
-Bu
(
R
)-configuration exhibited 0.55
antagonist, and a eudismic ratio of 8.2. Ethyl-branched
analog 9e with ( )-configuration showed a slightly a
µM of IC50 value as
9f
9g
R
less potent activity compared to 9c. However, in case
of the fluorinated analogs of SC-0030, ethyl-branched
analog 9g were more potent than methyl-branched
analog 9f. Among the tested compounds, fluorinated
ethyl-branched analog 9g showed the most potent
MK-056
SC-0030
H
H
aEC50 (the concentration of derivatives necessary to pro-
duce 50% of the maximal response) and IC50 values (the
concentration of derivatives necessary to reduce the
antagonist activity with an IC50 value of 0.41 µM. All
response to 0.5 µM capsaicin by 50%) were estimated with
at least three replicates at each concentration. Each com-
pound was tested in two independent experiments. Antag-
onist data were fitted with a sigmoidal function.
of chain branched analogs were less potent than the
parent compounds MK-056 and SC-0030, indicating
that chain branching on the benzylic position of B-ring
is detrimental to the potency. It is expected that re-
duction in lipophilicity resulted by chain branching 003, our report would serve as an important basis for
could be counterbalanced by the increased hydrocar- the development of the highly potent and novel TRPV1
bon moiety. Accordingly, a decrease in potency by antagonist with suitable pharmacological properties.
chain branching is due to the poor binding of analogs Further work on the therapeutically useful TRPV1
to the receptor, and not to the changed lipohilicities of antagonist based on our current results is underway.
the analogs. An increase in the bulk on the benzylic
position of B-ring seems to be weakening the receptor
binding. A high eudismic ratio of enantiomers provides
a piece of evidence that optimized receptor binding is
ACKNOWLEDGEMENTS
This Research was supported by the Sookmyung
interfered by chain branching, resulted in decrease in Women's University Research Grants 2009, and the
the potency of our analogs. While most of the analogs SRC program of KOSEF (Research Center for Women's
we explored failed to exhibit the improved their po- Diseases).
tency over the parent compounds MK-056 and SC-

326
M. Jang et al.
Discov. Today, 1, 97-104 (2004).
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