Design and evaluation of new antipsoriatic antedrug candidates having 16-en-22-oxa-vitamin D3 structures

Article abstract of DOI:10.1016/j.bmcl.2006.03.014

Design, synthesis, and in vitro and in vivo evaluation of a series of antipsoriatic antedrugs having 16-en-22-oxa-vitamin D₃ are described. Among the seven compounds examined, two are promising: ester 5c and amide 5f, both of which exhibit grea

Full text of DOI:10.1016/j.bmcl.2006.03.014

Bioorganic & Medicinal Chemistry Letters 16 (2006) 3323–3329
Design and evaluation of new antipsoriatic antedrug candidates
having 16-en-22-oxa-vitamin D3 structures
Kazuki Shimizu,* Akira Kawase, Tsuyoshi Haneishi, Yasuharu Kato,
Kazutomo Kinoshita, Masayuki Ohmori, Yoshiyuki Furuta, Takashi Emura,
Nobuaki Kato, Tetsuya Mitsui, Koji Yamaguchi, Keiichi Morita, Nobuo Sekiguchi,
Tessai Yamamoto, Tomochika Matsushita, Shin Shimaoka,
Atsuko Sugita and Kazumi Morikawa
Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
Received 12 October 2005; revised 20 February 2006; accepted 7 March 2006
Available online 21 April 2006
Abstract—Design, synthesis, and in vitro and in vivo evaluation of a series of antipsoriatic antedrugs having 16-en-22-oxa-vitamin
D3 are described. Among the seven compounds examined, two are promising: ester 5c and amide 5f, both of which exhibit greater
potent antiproliferation activity with lessened calcemic activity than the presently prescribed maxacalcitol (2).
ꢀ 2006 Elsevier Ltd. All rights reserved.
As therapeutic agents for intractable psoriasis with an
unknown cause, various steroids, retinoids, and immu-
nosuppressants such as cyclosporine and methotrexate
have been developed. However, these medicines have
severe side effects including rebound phenomenon,1
atrophy of skin,2,3 teratogenesis,4 nephrotoxicity,5 liver
fibrosis,6,7 and interstitial pneumonia.8 Since the rec-
ognition of the therapeutic effect of the naturally
occurring hormone calcitriol (1a,25-dihydroxyvitamin
However, these vitamin D agents show less efficacy than
steroids which belong to the ‘very strong’14 or ‘strongest’
class. High doses of vitamin D3 analogs induce an unde-
sirable calcemic action not found in steroids but exhibit
an efficacy closer to that of the potent steroids.15 These
findings prompted us to improve the safety of vitamin D
agents which would allow higher dosages.
Recently, we reported a series of 16-en-22-oxa-vitamin
D3 analogs16 which showed reduction of calcemic
activity. This reduction is assumed to be due to the rapid
oxidative metabolism of enzymes in liver that rapidly
converted the absorbed 16-en-22-oxa-vitamin D3
analogs into inactive metabolites after exhibiting cell
antiproliferative activity. The 16-en-22-oxa-vitamin D3
analogs were absorbed topically and assumed to be
oxidized at the allylic C20 or C23 center adjacent to
the oxygen atom rapidly after entering into liver through
systemic circulation, and gave rise, presumably via the
hemiacetal intermediates 6 or 8 from metabolic enzymes
in the liver, such as CYPs, to the inactive metabolite 7 or
9.16,17 This mode of action is in accordance with the
definition of an ‘antedrug,’18–20 an active synthetic
derivative designed to undergo biotransformation,
proposed in the early 1980s (Chart 2).
D3; 1, Chart 1) was reported in the early 1980s,9
a
number of studies10 have focused on the separation
of the antipsoriatic effect from the undesirable calce-
mic activity by modification of the natural structure
in order to develop a more favorable therapeutic
index. Side-chain analogs of calcitriol (1) such as
maxacalcitol (2),11 tacalcitol (3),12 and calcipotriol
(4)13 have been developed for clinical treatment of
psoriasis. Although they require careful administration
due to their calcemic effects, such vitamin D3 analogs
have been used extensively because they are safer than
other treatments.
Keywords:
16-En-22-oxa-24-carboalkoxide-1a,25-dihydroxyvitamin
D3 analogs; 16-En-22-oxa-24-carbamide-1a,25-dihydroxyvitamin D3
analogs; Antedrug; Low calcemic activity; Psoriasis.
*
With the antedrug concept in mind, we decided to design
a new 16-en-22-oxa-vitamin D3 antedrug having 24-ester
Corresponding author. Tel.: +81 550 87 6723; fax: +81 550 87
5326; e-mail: tazumikzk@chugai-pharm.co.jp
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.03.014

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K. Shimizu et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3323–3329
OH
OH
O
OH
OH
HO
OH
HO
OH
HO
OH
HO
OH
Calcipotriol (4)
Calcitriol (1)
Tacalcitol (3)
Maxacalcitol (2)
Chart 1. Structure of 1 and its analogs.
O
24
*
*
OH
O
23
X-R
OH
7
6
OH
O
O
24
X-R
O
O
*
O
20
X-R
16
X=O or NH
9
8
5
O
*
O
OH
5a
Chart 2. Presumed multipath metabolism of 16-en-22-oxa-24-carboalkoxy or carbamide analogs.
and 24-amide functionality. As it was known that calci-
triol (1) metabolized into biologically inactive calcitronic
acid (10),21 installing additional metabolic functionality
leading to inactive carboxy functionality would improve
the ‘antedrug’ profile (Chart 3). We were most interested
in a combination of the changes in the activities of the
newly combined analogs of 16-en, 22-oxa, and 24-carbo-
alkoxide or 24-carbamide moieties and reduction of the
metabolic stability by multipath metabolism. With mod-
ification at the terminal part of the side-chain, the unde-
sirable calcemic activity would be reduced through
faster metabolism in systemic circulation.
For comparison, 5g–i were also prepared and their
activities evaluated. The results from compounds 5c
and 5f provide promise of potent and selective topical
vitamin D antipsoriatic agents (Fig. 1).
The synthesis of 16-en-22-oxa-24-carboalkoxy and
16-en-22-oxa-24-carbamide analogs 5b–f is shown in
Scheme 1. Treatment of the allyl alcohol 1122 was first
transformed into the secosteroidal allyl alcohol 12 by
photocycloreversion and thermal hydrogen migration,
in 64% yield. The etherification of the allyl alcohol 12
with tert-butylacetate under standard Williamson condi-
tions gave the desired tert-butyl ester 13b, followed by
hydrolysis to obtain the common intermediate secoster-
oidal carboxylic acid 14. The condensation with appro-
priate alcohols or amines under standard conditions,
In this paper, we describe the synthesis and biological
profiles of 16-en-22-oxa-24-carboalkoxy, carbamide
analogs 5b–f, and the presumed metabolites 7 and 5a.
OH
OH
24
O
23
OH
24-hydroxylase
24
HO
O
OH
OH
HO
OH
Calcitronic acid (10)
Calcitriol (1)
Chart 3. Metabolic pathway of calcitriol (1).

K. Shimizu et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3323–3329
3325
Figure 1. In vivo serum total calcium concentration after 8-day topical administration of maxacalcitol (2), 5c, and 5f in rats.
followed by desilyation, furnished 16-en-22-oxa-24-car-
boalkoxy and 16-en-22-oxa-24-carbamide analogs 5b–f
in good yield without difficulty.
maxacalcitol (2) shown in Scheme 2. With the same
Williamson condition as step b in Scheme 1, the precur-
sor of photolysis, 5,7-dien-ester 17, was obtained. After
photolysis and deprotection, steroidal ester 17 furnished
22-oxa-24-carboalkoxy analog 5g.
We also synthesized the 16-en-22-oxa-24-carboxylic acid
5a, which is presumed to be the common metabolite of es-
ters 5b and 5c, and amides 5d–f for a comparison in the
biological evaluation. The synthesis utilized the interme-
diate 13b in the syntheses of 5b, 5c, 5e, and 5f. Thus, the
carboxylic acid 14 afforded the desired seco-steriod 5a
through 15a after removal of its bis TBS ether.
The 22-carbon analogs 5h and 5i were prepared starting
from the known diene 19h24 or triene 19i23 (Scheme 3).
Ene reaction of 19 with methyl propiolate using Et2AlCl
provided 22-en-steroidal ester 20. Reduction of triene
20h gave C16–C17 saturated analog 21h by H2 and
Pd–C, and reduction of tetraene 20i gave 5,7,16-trien
analog 21i by NiCl2 and NaBH4, respectively. 5-En
analog 21h converted into 5,7-diene by standard
Synthesis of 22-oxa-24-carboalkoxy analog 5g utilized
the secondary alcohol 16 formed in the synthesis23 of
O
O
OH
O
O
OH
X
OH
TBSO
a
b
c
13b: X=O
13d: X=NH
TBSO
11
12
OTBS TBSO
14
OTBS
TBSO
OTBS
TBSO
e
O
O
O
O
R
R
d
e
5a: R=OH
5b: R=OC(CH3)3
15a: R=OCH(CH3)2
5c: R=OC(CH3)(C2H5)2
5d: R=NHC(CH3)3
5e: R=NHCH2C(CH3)3
5f: R=NHCH2CF2CF3
15c: R=OC(CH3)(C2H5)2
15e: R=NHCH2C(CH3)3
15f: R=NHCH2CF2CF3
TBSO
OTBS
HO
OH
Scheme 1. Reagents and conditions: (a) hm, THF; heating; (b) method for 13b: NaH, 15-crown-5, tert-butyl bromoacetate, THF, method for 13d:
NaH, 15-crown-5, N-tert-butyl bromoacetamide, DMF, THF; (c) 1 M NaOMe, aq 1 M NaOH, MeOH, THF (69% from 12); (d) method for 15a:
propan-2-ol,2-chloro-1,3-dimethylimidazolinium chloride, pyridine, CH2Cl2, method for 15c: 3-methyl-3-pentanol, DCC, DMAP, CH2Cl2, method
for 15e: 2,2-dimethyl-propylamine,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride salt (WSCIÆHCl), HOBtÆH2O, CH2Cl2, method for
15f: 2,2,3,3,3-pentafluoro-propylamine, WSCIÆHCl, HOBtÆH2O, CH2Cl2, (e) 1 M TBAF, THF (5a: 33% from 14, 5b: 30%, 5c: 50% from 14, 5d: 20%
from 12, 5e: 40% from 14, and 5f: 77% from 14).

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K. Shimizu et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3323–3329
O
O
O
O
OH
O
O
TBSO
TBSO
a
b
18; R=TBS
5g; R=H
c
TBSO
TBSO
16
17
RO
OR
Scheme 2. Reagents and conditions: (a) NaH, 15-crown-5, tert-butyl bromoacetate, THF (17%); (b) hm, THF; heating; (c) HF–pyridine, THF (9%
from 17).
O
O
TBSO
O
21h; 5-ene
TBSO
O
b
TBSO
TBSO
O
a
O
TBSO
c
TBSO
TBSO
19h; 5-ene
19i; 5,7-diene
20h; 5-ene
20i; 5,7-diene
21i; 5,7,16-triene
TBSO
g
O
O
O
O
O
TBSO
OR
TBSO
d
g
i
26h,26i; R=TBS
5h, 5i; R=H
TBSO
22h
j
TBSO
TBSO
e
f
24h,24i; R=H
25h, 25i; R=C(CH3)3
h
23h
RO
OR
TBSO
N
N
O
N
O
Ph
Scheme 3. Reagents and conditions: (a) Et2AlCl in n-hexane, methyl propiolate, CH2Cl2 (20h: 84%, 20i: 23%); (b) 5% Pd–C, H2, AcOEt (98%); (c)
NaBH4, NiCl2Æ6H2O, THF, MeOH, (quant.); (d) NBS, AIBN, n-hexane; then c-collidine, toluene; (e) PTAD, CH2Cl2; (f) DMI, heating (17% from
21h); (g) aq 2 N NaOH, THF, MeOH (24h: 99%, 24i: 99%) (h) tert-butanol, DCC, DMAP, CH2Cl2; (i) hm, THF; heating; (j) method for 5h:
HF–pyridine, THF; (8% from 24h), method for 5i: 1 M TBAF, THF (1% from 24i).
conditions established in the synthesis of vitamin D3
derivatives,25,26 via allyl bromides. The crude dienes
22h were first treated with 4-phenyl-1,2,4-triazoline-
3,5-dione (PTAD)27 to give the corresponding PTAD
adduct 23h for purification. After retro-Diels–Alder
reaction, the pure 5,7-diene 22h was obtained. The 5,7-
dienes 22h and 21i furnished 22-carbon esters 5h and
5i after hydrolysis, ester condensation, photolysis, ther-
mal isomerization, and deprotection.
mic activity was estimated based on the calcemic
increment levels from in vivo mouse or rat percutane-
ous administration. The pharmacological activity was
estimated by measurement of human keratinocyte
growth inhibitory activity.28 A chicken VDR affinity
evaluation confirmed that the compounds function as
vitamin D analogs.
Table 1 shows the profiles of compound 5b and its
analogs 5i, 5g, and 5h. According to our previous stud-
ies,16 16-en-22-oxa-vitamin D3 analogs metabolized fast-
er than 2, shown by the profiles of the representative
analog 2a in Table 1. Introduction of a 24-ester moiety
into 16-en-22-oxa analogs like 5b increased the metabol-
ic rate. This result might be due to the multipath
metabolism, oxidative metabolism, and hydrolysis. A
comparison of 5b with 5i and of 5g with 5h clearly
showed that 22-oxa functionality largely contributed
to the poor metabolic stability. Interestingly, the
Biological activities of the compounds prepared in the
present study were evaluated as follows using 2 as
the reference: (i) in vitro metabolic stability, (ii) in vivo
calcemic activity, and (iii) in vitro pharmacological
activity. For in vitro metabolic stability, compounds
were incubated with rat liver microsomes or human liv-
er S9 in the presence of NADPH and the metabolic
elimination rate, ke, was determined by time course
for concentrations in the reaction mixture. The calce-

K. Shimizu et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3323–3329
Table 1. Biological activity of 16-en-22-oxa-vitamin D3 analogs
3327
O
O
O
O
O
O
O
O
O
O
O
OH
5b
5h
5i
5g
2a
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
Compound
VDR affinity Metabolic stability in In vivo blood Ratio of Ca change Antiproliferatior
(%)a
Antiproliferatior
activity IC50 (nM)k activity A (%) versus 1l
rat liver microsome
ke ratio versus 2b
ionized Ca
(mmol/L)c
to vehicle C (%)j
Calcitriol (1)
100
n.d.
1
n.d.
n.d.
98.5
66.2
22.2
28.3
67.4
9.6
27.3
22.6
50.4
8.9
100
120.5
54.1
Maxacalcitol (2)
20.0
n.d.
40.1
n.d.
n.d.
n.d.
2.60 0.22d
2.16 0.07e
1.65 0.05f
1.77 0.11g
2.31 0.18h
1.49 0.09i
2a16
5b
1.3
3.9
0.4
2.9
11.6
305.6
160.4
432.1
30.8
5h
17.0
6.3
5i
5g
88.4
n.d., not determined.
a Each point represents the average of duplicate measurements.
b Metabolic stability was calculated as the ratio of the ke value of the analog to 2. Values are means of two experiments.
c The in vivo calcemic activity of test compounds determined by measuring serum calcium level in mice after single percutaneous administration
(n = 3).
d Vehicle levels (mmol/L): 1.31 0.04.
e Vehicle levels (mmol/L): 1.30 0.05.
f Vehicle levels (mmol/L): 1.35 0.02.
g Vehicle levels (mmol/L):1.38 0.02.
h Vehicle levels (mmol/L): 1.38 0.03.
i Vehicle levels (mmol/L): 1.36 0.01.
j Calcemic activity (%) = {(blood ionized Ca [mmol/L] of the analogs) À (blood ionized Ca [mmol/L] of the vehicle)}/(blood ionized Ca [mmol/L] of
the vehicle)} · 100.
k The in vitro effect is expressed as percentage activity at IC50 (n = 2, mean value) in comparison with 1. IC50 is the molar concentration of the test
compound that causes 50% of the maximal inhibition of proliferation by suppression of [3H]TdR uptake.
l Antiproliferation activity (%) = {(IC50 [nM] of 1)/(IC50 [nM] of the analogs)} · 100.
antiproliferative activity appeared to be subjected to 16-
en substructure in comparing 5g with 5b and 5h with 5i.
Finally, the combination of 16-en, 22-oxa, and 24-ester
moieties is effective for enhancing the metabolic instabil-
ity as well as the pharmacological activity.
However, the metabolic stability of 5b and 5d was incon-
sistent with the general tendency of metabolic rates in es-
ters and amides.
To lower the calcemic activity of amide 5d, we promoted
metabolism by steric and electronic effects on the car-
bamide moiety. In 5e, steric hindrance around the nitro-
gen atom was removed, and in 5f, the elimination ability
of the amino group was accelerated by attachment of an
electronegative fluorine atom, and retained terminal
hydrophobicity in both. The enhancement of metabo-
lism and the reduction of calcemic activity in 5e and 5f
suggested that both steric and electronic effects may
have contributed to the promotion of hydrolysis. Addi-
tionally, the modifications of 5f may have markedly
increased antiproliferative activity.
Table 2 shows the profiles of substrates 5c–f and their
presumed metabolites 5a and 7. The 3-(3-methyl)-pentyl
ester 5c was designed based on the structure of the ‘super
agonist’ lexacalcitol10 having three substructures—epi-
merization at C20, insertion of methylene group at C24,
and insertion of methylene group at C26 and C27—which
seem to contribute to its potent activity. The increase of
terminal hydrophobicity in 5c with a 26,27-dihomo sub-
stitution obviously enhanced the metabolic instability,
reduced the calcemic activity, and increased the antipro-
liferative activity greatly. It occurred to us that the higher
hydrophobicity enhanced the affinity to CYP29 and the
terminal bulky substituent had some impact on VDR
signaling.30
Carboxylic acid 5a and alcohol 7 exhibited few activi-
ties, desirable or undesirable, indicating that these two
presumed metabolites were inactive, in accordance with
the antedrug concept.
Although amide 5d was metabolically unstable, calcemic
activity remained relatively potent. Undesirable calcemic
activity seems to be explained by a balance of metabolic
stability with biological activity. In the case of 5d, this
balance seems to be responsible for improved activity.
Of the antipsoriatic vitamin D3 analogs form this series,
the above results show that ester 5c and amide 5f were
found to have beneficial pharmacological activity and
only slight calcemic activity. Therefore, compounds 5c

3328
K. Shimizu et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3323–3329
Table 2. Biological activity of 16-en-22-oxa-vitamin D3 analogs
O
O
O
O
O
O
O
O
O
O
OH
O
N
H
N
H
N
H
OH
C2F5
5c
5d
5e
5f
5a
7
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
Compound
VDR affinity (%)a Metabolic stability in In vivo blood Ratio of Ca change Antiproliferatio
Antiproliferatior
activity IC50 (nM) activity A (%)
to vehicle Cj (%)
k
rat liver microsome
ke ratio versus 2b
ionized Ca
(mmol/L)c
versus 1l
Maxacalcitol (2) 20.0
1
>10
8.2
2.60 0.22d
1.57 0.03e
2.16 0.28f
1.82 0.08g
1.58 0.11h
1.38 0.04i
1.40 0.04i
98.5
9.8
22.6
0.8
120.5
3519.8
619.2
157.2
1470.7
<2.7
5c
5d
5e
5f
45.1
22.2
18.0
34.4
63.6
31.9
4.4
>10
14.4
n.d.
n.d.
17.4
1.9
16.2
No elevation
No elevation
5a
716
0.04
0.32
>1000
>1000
<2.7
n.d., not determined.
a,b,c,j,k,l
See Table 1.
d Vehicle levels (mmol/L): 1.31 0.04.
e Vehicle levels (mmol/L): 1.43 0.07.
f Vehicle levels (mmol/L): 1.32 0.02.
g Vehicle levels (mmol/L): 1.38 0.02.
h Vehicle levels (mmol/L): 1.36 0.01.
i Vehicle levels (mmol/L): 1.44 0.03.
Table 3. In vitro and in vivo pharmacokinetic parameters of maxacalcitol 2, 5c, and 5f
Compound
In vivo pharmacokinetic in ratsa
In vivo skin concentration after
percutaneous administration to rats
(3 mg/0.3 g ointment/kg)b concentration
ratio versus 2 (4 h)
In vitro metabolic
clearance in human liver
S9 (mL/min/mg S9 protein)c
Dose (lg/kg)
CLtot (mL/h/kg)
Maxacalcitol (2)
10
1000
1000
1257
5691
7853
1
0.007
1.421
0.278
5c
5f
0.8
0.6
a Values represent means of several rats: 2: n = 4, 5c: n = 3, 5f: n = 3.
b Single percutaneous administration (after 4 h).Values are means of two rats.
c Values are means of two experiments.
and 5f were further evaluated in pharmacokinetic stud-
ies and their calcemic activities examined in detail.
In summary, we prepared and profiled a series of 16-en-
22-oxa vitamin D3 analogs possessing a 24-carboalkox-
ide or 24-carbamide moiety in the side-chain, with the
expected enhancement of the metabolic instability fol-
lowed by conversion to inactive metabolites. This series
has shown to be extremely potent agonists of VDR with
low calcemic action. Further biological evaluation of
these analogs identified compounds 5c and 5f to be
extremely potent, low-calcemic vitamin D3 analogs, with
concentration in rat skin comparable to maxacalcitol
(2). Compounds 5c and 5f are currently being evaluated
in further detail for their clinical application as antipso-
riatic agents.
Table 3 shows the pharmacokinetic profiles for the
in vitro and in vivo studies of maxacalcitol (2), 5c, and
5f. After intravenous dosing to rats, 5c and 5f had great-
er clearance than 2, similar to the results of the stability
evaluation in rat microsomes. The in vivo rat skin con-
centrations after percutaneous administration were al-
most equal to 2, indicating that highly potent analogs
5c and 5f would exhibit higher efficacy than 2 at the
same dose.
In human liver S9, 5c and 5f proved quite unstable met-
abolically compared with 2, indicating that these two
compounds also metabolized rapidly in human liver.
Acknowledgments
The calcemic activity of 5c and 5f were further assessed
in an 8-day percutaneous administration study. The
results from rats treated with 5c and 5f at several dosag-
es exhibited clear reduced calcemic activity over maxa-
calcitol (2).
We gratefully thank Dr. Kunio Ogasawara, Professor
Emeritus, Tohoku University, for his helpful suggestions.
We thank Mr. Kenichiro Kotake, Ms. Ikumi Tanabe, and
Ms. Miyuki Yagi for HRMS measurements of the
compounds. We also thank Mr. Toshiro Kozono,

K. Shimizu et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3323–3329
3329
van de Kerkhof, P. C.; Hanssen, L. I.; Tegner, E.; Burg,
G.; Talbot, D.; Chu, A. J. Am. Acad. Dermatol. 2003, 48,
48.
Dr. Tadakatsu Takahashi, Mr. Toru Esaki, Dr. Masaki
Ishigai, Dr. Kosuke Kawashima, Mr. Shohtaro Takada,
Mr. Nobuo Koike, Mr. Kazuo Tokuda, Dr. Eigoro
Murayama, and Dr. Noboru Kubodera in Chugai Phar-
maceutical Co., Ltd, for their advice and encouragement.
We acknowledge Ms. Frances Ford in Chugai for her use-
ful advice in the preparation and language editing of this
paper.
15. Bourke, J. F.; Berth-Jones, J.; Iqbal, S. J.; Hutchinson, P.
E. Br. J. Dermatol. 1993, 129, 74.
16. Shimizu, K.; Kawase, A.; Haneishi, T.; Kato, Y.; Kobay-
ashi, T.; Sekiguchi, N.; Yamamoto, T.; Ishigai, M.;
Tokuda, K.; Matsushita, T.; Shimaoka, S.; Morikawa,
K. Bioorg. Med. Chem 2006, 14, 1838.
17. Watanabe, H.; Hatakeyama, S.; Tazumi, K.; Takano, S.;
Masuda, S.; Okano, T.; Kobayashi, T.; Kubodera, N.
Chem. Pharm. Bull. 1996, 44, 2280.
18. Antedrug is a locally active synthetic derivative of a drug
undergoing biotransformations to readily excretable inac-
tive form upon entry in the systemic circulation thus
minimizing systemic side effects Lee, H. J.; Soliman, M. R.
Science 1982, 215, 989.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.bmcl.2006.03.014.
19. It was also called as ‘soft drug.’ See Bodor, N. Med. Res.
Rev. 1984, 4, 449.
20. Kimura, T. Nippon Rinsho 1994, 52, 691.
21. Esvelt, R. P.; De Luca, H. F. Arch. Biochem. Biophys.
1981, 206, 403.
22. Kawase, A. JP Patent 10-231284, 1998.
23. Shimizu, H.; Shimizu, K.; Kubodera, N.; Mikami, T.;
Tsuzaki, K.; Suwa, H.; Harada, K.; Hiraide, A.; Shimizu,
M.; Koyama, K.; Ichikawa, Y.; Hirasawa, D.; Kito, Y.;
Kobayashi, M.; Kigawa, M.; Kato, M.; Kozono, T.;
Tanaka, H.; Tanabe, M.; Iguchi, M.; Yoshida, M. Org.
Process Res. Dev. 2005, 9, 278.
24. Kubodera, N. Yuki Gosei Kagaku Kyokaishi 2005, 63,
728.
25. Zhu, G.-D.; Okamura, W. H. Chem. Rev. 1995, 95,
1877.
26. Kubodera, N.; Miyamoto, K.; Ochi, K.; Matsunaga, I.
Chem. Pharm. Bull. 1986, 34, 2286.
27. Kubodera, N.; Miyamoto, K.; Watanabe, H.; Kato,
M.; Sasahara, K.; Ochi, K. J. Org. Chem. 1992, 57,
5019.
References and notes
1. Zheng, P. S.; Lavker, R. M.; Lehmann, P.; Kligman, A.
M. J. Invest. Dermatol. 1984, 82, 345.
2. DiStefano, V.; Nixon, J. E. Clin. Orthop. 1972, 87, 254.
3. Foldvari, F.; Vertes, B. Fulope Dermatol. 1962, 125, 93.
4. Kamm, J. J. J. Am. Acad. Dermatol. 1982, 6, 652.
5. Flechner, S. M. Urol. Clin. North Am. 1983, 10, 263.
6. Nyfors, A.; Poulsen, H. Acta Pathol. Microbiol. Scand.
[A] 1976, 84, 262.
7. Nyfors, A.; Poulsen, H. Acta Pathol. Microbiol. Scand.
[A] 1976, 84, 253.
8. Imokawa, S.; Colby, T. V.; Leslie, K. O.; Helmers, R. A.
Eur. Respir. J. 2000, 15, 373.
9. Tanaka, H.; Abe, E.; Miyaura, C.; Kuribayashi, T.; Konno,
K.; Nishii, Y.; Suda, T. Biochem. J. 1982, 204, 713.
10. Bouillon, R.; Okamura, W. H.; Norman, A. W. Endocr.
Rev. 1995, 16, 200.
11. Murayama, E.; Miyamoto, K.; Kubodera, N.; Mori, T.;
Matsunaga, I. Chem. Pharm. Bull. 1986, 34, 4410.
12. Morisaki, M.; Koizumi, N.; Ikekawa, N.; Takeshita, T.;
Ishimoto, S. J. Chem. Soc., Perkin Trans. 1 1975, 1421.
13. Binderup, L.; Bramm, E. Biochem. Pharmacol. 1988, 37,
889.
28. Nagpal, S.; Lu, J.; Boehm, M. F. Curr. Med. Chem. 2001,
8, 1661.
29. Lewis, D. F. V.; Dickins, M. Drug Metab. Rev. 2003,
35, 1.
30. Takeyama, K.; Masuhiro, Y.; Fuse, H.; Endoh, H.;
Murayama, A.; Kitanaka, S.; Suzawa, M.; Yanagisawa,
J.; Kato, S. Mol. Cell. Biol. 1999, 19, 1049.
14. Papp, K. A.; Guenther, L.; Boyden, B.; Larsen, F. G.;
Harvima, R. J.; Guilhou, J. J.; Kaufmann, R.; Rogers, S.;