Analysis of structure-activity relationships for the 'A-region' of N-(4-t-butylbenzyl)-N′-[4-(methylsulfonylamino)benzyl]thiourea analogues as TRPV1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2005.06.009

The structure-activity relationships for the 'A-region' of N-(4-t-butylbenzyl)-N′-[4-(methylsulfonylamino)benzyl]thiourea analogues have been investigated as TRPV1 receptor antagonists. The 2-halogen analogues showed enhanced antagonism compared to the prototype antagonist.

Full text of DOI:10.1016/j.bmcl.2005.06.009

Bioorganic & Medicinal Chemistry Letters 15 (2005) 4136–4142
Analysis of structure–activity relationships for the ÔA-regionÕ
of N-(4-t-butylbenzyl)-N0-[4-(methylsulfonylamino)benzyl]thiourea
analogues as TRPV1 antagonists
a
a
a
a
Jeewoo Lee,a,b, Sang-Uk Kang, Min-Jung Kil, Myoungyoup Shin, Ju-Ok Lim,
*
Hyun-Kyung Choi,a Mi-Kyoung Jin,a Su Yeon Kim,a Sung-Eun Kim,a Yong-Sil Lee,a
Kyung-Hoon Min,a Young-Ho Kim,b Hee-Jin Ha,b Richard Tran,c Jacqueline D. Welter,c
Yun Wang,c Tamas Szabo,c Larry V. Pearce,c Daniel J. Lundberg,c Attila Toth,c
Vladimir A. Pavlyukovets,c Matthew A. Morganc and Peter M. Blumbergc
aResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
bDigitalbiotech, Ansan, Kyounggi-Do 425-839, Republic of Korea
cLaboratory of Cellular Carcinogenesis and Tumor Promotion, Center for Cancer Research, National Cancer Institute,
NIH, Bethesda, MD 20892, USA
Received 9 March 2005; revised 1 June 2005; accepted 2 June 2005
Available online 6 July 2005
Abstract—The structure–activity relationships for the ÔA-regionÕ of N-(4-t-butylbenzyl)-N0-[4-(methylsulfonylamino)benzyl]thio-
urea analogues have been investigated as TRPV1 receptor antagonists. The 2-halogen analogues showed enhanced antagonism
compared to the prototype antagonist.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
TRPV1 is activated by protons,9 heat,4 endogenous sub-
stances such as anandamide10 and the lipoxygenase
products,11 and natural ligands such as capsaicin
(CAP)12 and resiniferatoxin (RTX).13 Since 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 excita-
tion of primary sensory neurons and ultimately the cen-
tral perception of pain. The involvement of this receptor
in both pathological and physiological conditions sug-
gests that the blocking of this receptor activation, by
desensitization or antagonism, would have considerable
therapeutic utility. Among its therapeutic targets, pain is
of particular interest. The validation of TRPV1 as a
molecular target for the treatment of chronic pain was
confirmed using transgenic mice lacking functional
TRPV1 receptors. These mice exhibited impairment in
the perception of thermal and inflammatory pain.14
The vanilloid receptor subtype 1 (VR1 or TRPV1)1 be-
longs to the transient receptor potential (TRP) super-
family. Members of this family are nonvoltage
activated cation channel proteins and share a structural
characteristic of six transmembrane segments.2,3 The
receptor has been cloned from dorsal root ganglia
(DRG) of the rat,4 the human,5 the chicken,6 the guinea
pig,7 and the rabbit.8 Other vanilloid receptor homo-
logues were also cloned recently from different organ-
isms but are not believed to be sensitive to vanilloids.2
TRPV1 is a molecular integrator of nociceptive stimuli
expressed predominantly on unmyelinated pain-sensing
nerve fibers (C-fibers) and small Ad fibers in the dorsal
root, trigeminal, and nodose ganglia.
TRPV1 antagonists have attracted much attention as
promising drug candidates to inhibit the transmission
of painful signals from the periphery to the CNS and
to block other pathological states associated with this
Keywords: TRPV1 antagonist; Vanilloid receptor 1 antagonist; Cap-
saicin; Resiniferatoxin.
*
Corresponding author. Tel.: +82 2 880 7846; fax: +82 2 888 0649;
e-mail: jeewoo@snu.ac.kr
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.06.009

J. Lee et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4136–4142
4137
receptor. The therapeutical advantage of TRPV1 antag-
onism over agonism is that it lacks the initial excitatory
effect preceding the desensitization. The initial acute
pain associated with capsaicin treatment has proven to
be the limiting toxicity.
(Ki = 50.4 nM, 17.4% agonism and 84.1% antagonism
in rTRPV1/CHO).19
In order to optimize in vitro activities of 4-methylsulf-
onamide TRPV1 antagonists, we have investigated their
structure–activity relationships based on the structural
regions designated as A-, B- and C-regions.20The exten-
sive modification of the C-region led to the finding that
4-t-butylbenzyl is one of the most favorable groups for
high receptor binding affinity and potent antagonism
of TRPV1.21 As a continuation of our effort, we herein
describe the structure–activity relationships in the A-re-
gion of the high affinity lead compounds 2–4 in which
the B- and C-regions of the novel ligands were fixed as
thiourea and 4-t-butylbenzyl groups, respectively.
Previously, we have demonstrated that isosteric replace-
ment of the phenolic hydroxyl group in potent vanilloid
receptor agonists with the alkylsulfonamido group gen-
erated compounds which were effective antagonists of
the action of capsaicin on rat TRPV1.15,16 As shown
in Figure 1, substitution of 4-hydroxy-3-methoxyphenyl
in the potent agonist 117 with 4-(methylsulfonylami-
no)phenyl led to a prototype antagonist 2,15 which
showed high binding affinity and potent antagonism
(Ki = 63 nM and Ki(ant) = 54 nM in rTRPV1/CHO).
We have further described that 3-substitutents in the
A-region affected the extent of agonism/antagonism.
2. Chemistry
Thus, the 3-fluoro derivative
3
(Ki = 53.5 nM,
Ki(ant) = 9.16 nM in rTRPV1/CHO15; IC50 = 37 nM in
rTRPV1/DRG18) was a potent antagonist not only of
capsaicin stimulation of rTRPV1 but also of stimulation
by temperature and pH. Conversely, the 3-methoxy
The target compounds were synthesized in general by the
coupling of 4-t-butylbenzyl isothiocyanate with the cor-
responding amines of the A-region. The syntheses of 2-
or 3-substituted analogues are outlined in Scheme 1.
Starting from commercially available 4-methylanilines,
the corresponding benzyl azides were prepared by t-bu-
toxycarbonyl protection of the amines, benzylic bromin-
ation (or hydroxylation), followed by conversion to
azides. The azides were reduced and finally coupled with
isothiocyanate to afford the thioureas 5–8 and 10–11.
The 3-hydroxy (9) and 2-trifluoromethyl (12) analogues
were prepared from 4-amino-3-hydroxybenzoic acid
and 4-bromo-3-(trifluoromethyl)aniline, respectively, by
straightforward conventional routes as described in
Schemes 2 and 3. The 3-methylsulfonylamino (13) and
4-(methylsulfonylamino)methyl (14) analogues were ob-
tained readily from the amines previously reported.16
The syntheses of 3-methylsulfide, sulfoxide and sulfone
analogues (15–17), shown in Scheme 4 started from 3-
mercaptobenzoic acid, which was converted to benzyl
azides with different oxidation states of sulfur. The
N-4-(methylsulfonylamino)phenyl (18) and N-4-(methyl-
sulfonylamino)phenethyl (19) analogues were prepared
derivative
4 showed a shift to partial agonism
Figure 1.
Scheme 1. Reagents: (a) for 5, 6: (Boc)2O, NaH, DMF, 85–95%; for 7: (i) NaSCH3, THF–dH2O; (ii) Fe, AcOH; (iii) (Boc)2O, EtOH; (iv) m-CPBA,
CHCl3, 40% for 4 steps; for 8: (i) (Boc)2O, CH2Cl2; (ii) (CH3)2CHBr, K2CO3, DMF, 82% for 2 steps; for 10, 11: (Boc) 2O, THF, 90–95%; (b) NBS,
AIBN, CCl4, 40–60%; (c) NaN3, DMF, 90–98%; (d) TFA, CH2Cl2; (e) MsCl, pyridine, 90–94% for 2 steps; (f) H2, Pd–C, MeOH or PPh3, H2O, THF,
92–98%; (g) (4-t-Bu)PhCH2NCS, NEt3, DMF, 75–95%.

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J. Lee et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4136–4142
Scheme 2. Reagents: (a) H2SO4, MeOH, 76%; (b) MsCl, CH2Cl2, 85%; (c) LiAlH4, THF, 88%; (d) NaN3, BF3–Et2O, dioxane, 82%; (e) H2, Pd–C,
MeOH, 98%; (f) (4-t-Bu)PhCH2NCS, NEt3, DMF, 92%.
Scheme 5. Reagents: (a) MsCl, pyridine, 99%; (b) H2, Pd–C, MeOH,
98%; (c) (4-t-Bu)PhCH2NCS, CH2Cl2, 94%.
Scheme 3. Reagents: (a) MsCl, pyridine, 98%; (b) CuCN, NMP,
185 °C, 76%; (c) H2, PdAC, MeOH, 98%; (d) (4-t-Bu)PhCH2NCS,
NEt3, CH2Cl2, 90%.
starting from 4-nitroaniline and 4-nitrophenylaceto
nitrile, respectively, in a conventional manner, as de-
scribed in Schemes 5 and 6. The syntheses of sulfonyl-
amino analogues 20–23 are depicted in Scheme 7. While
the sulfamide analogue (20) was prepared through N-
sulfonylation of N-Boc-4-aminobenzyl amine with sulfa-
myl chloride, compounds 21–23 were obtained through
key steps including N-sulfonylation with 2-chloro-
ethylsulfonyl chloride to provide (vinylsulfonyl)amino
and subsequent azidation with trimethylsilyl azide. The
syntheses of heterocyclic analogues are shown in
Schemes 8 and 9. Whereas the 2-methylsulfonylamino
pyridine analogue (24) was synthesized from 2-amino-
5-bromopyridine using a route similar to that described
in Scheme 3, the 5-methylsulfonylamino pyridine (25)
Scheme 6. Reagents: (a) H2, Pd–C, MeOH, 99%; (b) MsCl, pyridine,
92%; (c) H2, Pd–C, conc. HCl, MeOH, 40%; (d) (4-t-Bu)PhCH2NCS,
CH2Cl2, 88%.
and pyrazine (26) analogues were prepared from 6-meth-
yl nicotinic acid and 5-methyl-2-pyrazine carboxylic
acid, respectively, employing Curtius rearrangement
Scheme 4. Reagents: (a) CH3I, K2CO3, acetone, 98%; (b) LiAlH4, THF, 96%; (c) DPPA, DEAD, PPh3, THF, 68%; (d) H2O2, AcOH, 85% for n = 1;
(e) m-CPBA, CHCl3, 65% for n = 2; (f) H2, Pd–C, MeOH, 96%; (g) (4-t-Bu)PhCH2NCS, CH2Cl2, 92%.

J. Lee et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4136–4142
4139
Scheme 7. Reagents: (a) (Boc)2O, THF, 90%; (b) ClSO2NH2, Et3N, CH2Cl2, 60%; (c) ClSO2CH2CH2Cl, Et3N, CH2Cl2, 97%; (d) TMSN3, MeOH,
DMF, sealed tube, 100 °C, 75%; (e) CF3CO2H, CH2Cl2; (f) (4-t-Bu)PhCH2NCS, NEt3, CH2Cl2, 80–90% for 2 steps; (g) PPh3, H2O, THF, 80%.
vitro by a binding competition assay with [3H]RTX
and a functional 45Ca2+ uptake assay using rat TRPV1
heterologously expressed in Chinese hamster ovary
(CHO) cells, as previously described.15,16 The results
are summarized in Tables 1 and 2, together with the
potencies of capsazepine and the antagonists 2–4.
Our previous findings on the SAR of N-(4-t-butylben-
zyl)-N0-4-[(methylsulfonylamino)benzyl]thiourea antag-
onists indicated that the incorporation of 3-fluoro on
the A-region further enhanced antagonism, whereas a
Scheme 8. Reagents: (a) (CH3SO2)O, CH2Cl2, 55%; (b) CuCN, NMP,
3-methoxy group favored agonism. Therefore, we decid-
180 °C, 60%; (c) H2, Pd–C, conc. HCl, MeOH; (d) (4-t-
ed to explore the effect on potency as well as agonism/
Bu)PhCH2NCS, NEt3, CH2Cl2, 50% for 2 steps.
antagonism of substituents at various positions in the
A-region. The incorporation of electron-withdrawing
and the benzylic azidation method described in
Scheme 1.
groups, including the lipophilic 3-chloro (5, +r, +p),
3-nitro (6, +r, +p) and hydrophilic 3-methylsulfone (7,
+r, ꢀp), led to much reduced potencies in binding affin-
ity (>20-fold lower) and antagonism (>7-fold lower)
compared to 2. Indeed, the 3-methylsulfone analogue
(7) was devoid of any receptor activity. The analogues
with electron-donating groups, such as the lipophilic 3-
isopropoxy (8) and hydrophilic 3-hydroxy (9), showed
3. Results and discussion
The binding affinities and agonistic/antagonistic poten-
cies of the synthesized TRPV1 ligands were assessed in
Scheme 9. Reagents: (a) DPPA, Et3N, t-BuOH, toluene, 85%; (b) m-CPBA, CHCl3, 45%; (c) MsCl, Et3N, CH2Cl2, 78%; (d) NaN3, DMF, 80% in
X = C, 85% in X = N; (e) NBS, AlBN, CCl4, 80%; (f) CF3CO2H, CH2Cl2, 82%; (g) MsCl, pyridine, 60%; (h) H2, Lindler cat, MeOH; (i) (4-t-
Bu)PhCH2NCS, NEt3, DMF, 80% for 2 steps.

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J. Lee et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4136–4142
Table 1. Potencies of TRPV1 ligands for binding to rat VR1 and for inducing calcium influx in VR1/CHO cells
R1
R2
R3
Ki (nM)c binding affinity
EC50 (nM)c agonism
Ki (nM)c antagonism
CPZ
2
1300
63 ( 10)
NE
NE
520
NHSO2CH3
NHSO2CH3
NHSO2CH3
NHSO2CH3
NHSO2CH3
NHSO2CH3
NHSO2CH3
NHSO2CH3
NHSO2CH3
NHSO2CH3
NHSO2CH3
H
H
H
H
H
H
H
H
H
H
F
54 ( 8.7)
9.16 ( 1.6)
3.4 ( 0.5)b
400 ( 220)
610 ( 160)
NE
3
F
53.5 ( 6.5)
50.4 ( 16.5)
1160 ( 110)
1300 ( 120)
NE
NE
4
OCH3
Cl
NO2
WEa
NE
5
6
NE
NE
7
SO2CH3
OCH(CH3)2
OH
8
8072 ( 1900)
750 ( 72)
215 ( 19)
144 ( 31)
440 ( 56)
6000 ( 1200)
6120 ( 260)
580 ( 26.4)
3600 ( 1100)
1000 ( 23)
NE
3600 ( 1100)
WEb
9
WEa
NE
10
11
12
13
14
15
16
17
H
27.3 ( 8.6)
45.5 ( 2)
119 ( 21)
NE
H
Cl
CF3
H
H
H
H
H
NE
NE
H
NHSO2CH3
H
4100 ( 1500)
1720 ( 330)
WEa
CH2NHSO2CH3
H
NE
NE
SCH3
SOCH3
SO2CH3
H
1890 ( 190)
1010 ( 46)
NE
NE
H
a Only fractional calcium uptake compared with that induced by 300 nM capsaicin (4, 17%; 9, 62%; 15, 23%).
b Only fractional antagonism (4, 84%; 9, 39%).
c Values represent means SEM from three or more experiments (Ki for 8 represents means range of two experiments). NE, no effect. WE, weak
effect (quantitation of fractional agonism/antagonism is from 1–3 experiments; compounds were tested at a maximal concentration of 10–30 lM).
very low potencies both for binding and antagonism.
These findings indicated that steric factors at the 3-posi-
tion rather than electronic/lipophilic ones were most
important for receptor activity, since receptor potencies
diminished in proportion to the size of the 3-substitu-
ents. The small 3-substituents, such as hydrogen, fluoro
and methoxy groups in 2–4, were thus optimal for con-
ferring potent binding activity in this study.
in the A-region.22 Thus, 3-methylsulfide, sulfoxide and
sulfone analogues (15–17) were investigated as its cong-
eners. Interestingly, these congeners showed agonism
rather than antagonism even though 15 was found to
be a partial agonist. Moreover, their binding affinities
were low.
To find the optimal pharmacophoric distance between
the A- and B-regions, we varied the distance with a
one-carbon shortened 4-(methylsulfonylamino)phenyl
(18) and a one-carbon elongated 4-(methylsulfonylami-
no)phenethyl (19) analogues. These also displayed a dra-
matic decrease in binding affinity and antagonism with
limited partial agonism.
The effect of substituents at the 2-position was also
investigated. The 2-fluoro analogue of 2 (10) exhibited
3.5-fold weaker potency in binding affinity but 2-fold
greater potency for antagonism compared to 2. The
other electron-withdrawing groups, such as 2-chloro
(11) and 2-trifluoromethyl (12), led to moderately re-
duced binding affinity (2- and 7-fold) but retention of
potencies for antagonism. The modification of substitu-
ents in the A-region revealed that the 3-fluoro group ap-
peared to be optimal for binding and antagonism to the
receptor.
From our previous SAR investigation on the 4-meth-
ylsulfonylamino group, we demonstrated that substitu-
tion of methyl with other alkyl groups diminished the
potencies of binding and antagonism as the sizes in-
creased.16,23 In capsaicinoid agonists, a 2-aminoethyl
group has been employed on the phenolic hydroxyl
group of the A-region. The suggested rationale is that
this substitution enhances metabolic stability in vivo,
and the analogues indeed were orally effective with good
analgesic potency.17 Thus, we replaced the methyl group
of 4-methylsulfonamido with other groups such as
amine, vinyl, 2-azidoethyl and 2-aminoethyl to provide
20–23. Unlike the methylsulfonamide derivative, the sul-
famide (20) and vinylsulfonamide (21) congeners func-
tionally proved to be a partial and a full agonist,
respectively, with 10- and 3.5-fold reduced binding affin-
ity compared to 2. It is noteworthy that, although sub-
stitution of the 4-phenolic hydroxyl of the A-region in
agonists with the 4-methylsulfonamido group shifted
the ligands from agonism toward antagonism, the
In order to discern the positional significance of the 4-
methylsulfonylamino group in prototype 2 for antago-
nism, the corresponding 3-methylsulfonylamino (13)
and one-carbon elongated, 4-(methylsulfonylami-
no)methyl, analogues (14) were examined. As expect-
ed, both exhibited
a dramatic loss in binding
affinity, ca. 100-fold compared to 2, as well as a shift
to full agonism. This result is consistent with a series
of N-(3-acyl-2-benzylpropyl)thiourea analogues report-
ed previously.16
Recently, SB-366791 identified through high-throughout
screening was a potent and selective hTRPV1 antago-
nist; structurally, it contains a 3-methoxyphenyl group

J. Lee et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4136–4142
4141
Table 2. Potencies of TRPV1 ligands for binding to rat VR1 and for inducing calcium influx in VR1/CHO cells
R
Ki (nM)c binding affinity
EC50 (nM)c agonism
NE
Ki (nM)c antagonism
2
18
19
20
21
22
23
24
25
26
63 ( 10)
54 ( 8.7)
6800 ( 2800)
699 ( 81)
WEb
9560 ( 810)
3900 ( 1100)
650 ( 140)
231 ( 90)
WEa
WEa
WEa
250 ( 35.5)
NE
NE
145 ( 5.4)
4640 ( 210)
4100 ( 1300)
11900 ( 3900)
NE
231 ( 33)
NE
WEb
NE
177 ( 25)
4100 ( 900)
NE
NE
NE
a Only fractional calcium uptake compared with that induced by 300 nM capsaicin (18, 7%; 19, 18%; 20, 50%).
b Only fractional antagonism (20, 35%; 23, 50%).
c Values represent means SEM from three or more experiments. NE, no effect. WE, weak effect (quantitation of fractional agonism/antagonism is
from 1 to 3 experiments; compounds were tested at a maximal concentration of 10-30 lM).
antagonism can be restored to agonism by even small
modifications such as transposition to the 3-position
(13), one-carbon elongation (14) and substitution of
methyl with vinyl (21). The 2-azidoethyl congener (22)
was an antagonist with moderately reduced binding
affinity (2-fold) and antagonism (4-fold), whereas the
2-aminoethyl congener (23) was a partial antagonist
with much reduced binding affinity (75-fold) compared
to 2. The result confirmed that other sulfonamides did
not improve the potency of methylsulfonamide for
receptor antagonism.
BCTC,24 have been reported to show potent TRPV1
antagonism. Unfortunately, the pyridine analogues (24
and 25) exhibited much decreased receptor potencies
compared to 2 and the pyrazine analogue (26) was de-
void of activity.
In summary, we have modified the A-region of N-(4-t-
butylbenzyl)-N0-[4-(methylsulfonylamino)benzyl]thiourea
(2), a prototype TRPV1 antagonist with potent antago-
nism and high affinity, to analyze its structure–activity
relationships. The approaches included incorporation
of diverse substituents at the 2- and 3-positions, posi-
tional modification of 4-methylsulfonamide, 3-methoxy-
phenyl surrogates, variation of the distance between
A- and B-regions, methyl modification of 4-methylsulf-
onamide and phenyl substitution with isosteric rings.
As a last series of modifications, we replaced the phenyl
ring of 2 with polar isosteres, such as pyridine and pyr-
azine, for which one might expect improved pharmaco-
kinetics. A series of 4-(2-pyridyl)piperazines, such as

4142
J. Lee et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4136–4142
11. Hwang, S. W.; Cho, H.; Kwak, J.; Lee, S. Y.; Kang, C. J.;
Jung, J.; Cho, S.; Min, K. H.; Suh, Y. G.; Kim, D.; Oh, U.
Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 6155.
12. Walpole, C. S. J.; Wrigglesworth, R. Capsaicin in the
Study of Pain; Academic Press: San Diego, CA, 1993,
pp. 63.
The 2-halogen analogues, namely 10 and 11, showed en-
hanced antagonism. However, the other modifications
generally conferred modest to the dramatic decreases
in binding affinities and antagonistic potencies or shifted
ligands from antagonism to agonism.
13. Appendino, G.; Szallasi, A. Life Sci. 1997, 60, 681.
14. 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.
15. Wang, Y.; Szabo, T.; Welter, J. D.; Toth, A.; Tran, R.;
Lee, J.; Kang, S. U.; Lee, Y.-S.; Min, K. H.; Suh, Y.-G.;
Park, M.-K.; Park, H.-G.; Park, Y.-H.; Kim, H.-D.; Oh,
U.; Blumberg, P. M.; Lee, J. Mol. Pharm. 2002, 62, 947,
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16. Lee, J.; Lee, J.; Kang, M.; Shin, M.-Y.; Kim, J.-M.; Kang,
S.-U.; Lim, J.-O.; Choi, H.-K.; Suh, Y.-G.; Park, H.-G.;
Oh, U.; Kim, H.-D.; Park, Y.-H.; Ha, H.-J.; Kim, Y.-H.;
Toth, A.; Wang, Y.; Tran, R.; Pearce, L. V.; Lundberg, D.
J.; Blumberg, P. M. J. Med. Chem. 2003, 46, 3116.
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E. A.; Dray, A.; Hughes, G. A.; James, I.; Masdin, K. J.;
Winter, J. J. Med. Chem. 1996, 39, 4942.
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H.-S.; Kim, H.-D.; Park, H.-G.; Choi, J.-Y.; Lee, J.;
Kang, S.-W.; Oh, U.-T.; Koo, J.-Y.; Joo, Y.-H.; Kim,
S.-Y.; Kim, J. K.; Park, Y.-H. Bioorg. Med. Chem. Lett.
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In the following paper, the extensive structure–activity
relationships at the B-region will be described.
Acknowledgment
This work was supported by Grant R01-2004-000-
10132-0 from the Basic Research Program of the Korea
Science and Engineering Foundation.
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