Synthesis and PTP1B inhibition of 1,2-naphthoquinone derivatives as potent anti-diabetic agents.

Article abstract of DOI:10.1016/S0960-894X(02)00331-1

A new series of 1,2-naphthoquinone derivatives was synthesized by various synthetic methods and evaluated for their ability to inhibit protein tyrosine phosphatase 1B (PTP1B). 1,2-Naphthoquinone derivatives with substituent at R(4) position showed submicromolar inhibitory activity, and compound 24 demonstrated 10- to 60-fold selectivity against the tested phosphatases. Also, several 4-aryl-1,2-naphthoquinone derivatives with substituents at R(3), R(6), R(7), or/and R(8) showed submicromolar inhibitory activity and good plasma stability.

Full text of DOI:10.1016/S0960-894X(02)00331-1

Bioorganic & Medicinal Chemistry Letters 12 (2002) 1941–1946
Synthesis and PTP1B Inhibition of 1,2-Naphthoquinone
Derivatives as Potent Anti-Diabetic Agents
Jin Hee Ahn,y Sung Yun Cho,y Jae Du Ha,y So Young Chu, Sun Ho Jung,
Yoon Sung Jung, Ji Yoen Baek, In Kyung Choi, Eun Young Shin, Seung Kyu Kang,
Sung Soo Kim, Hyae Gyeong Cheon, Sung-Don Yang and Joong-Kwon Choi*
Medicinal Science Division, Korea Research Institute of Chemical Technology, Taejon, 305-600, Republic of Korea
Received 5March 2002; accepted 6 May 2002
Abstract—A new series of 1,2-naphthoquinone derivatives was synthesized by various synthetic methods and evaluated for their
ability to inhibit protein tyrosine phosphatase 1B (PTP1B). 1,2-Naphthoquinone derivatives with substituent at R4 position showed
submicromolar inhibitory activity, and compound 24 demonstrated 10- to 60-fold selectivity against the tested phosphatases. Also,
several 4-aryl-1,2-naphthoquinone derivatives with substituents at R3, R6, R7, or/and R8 showed submicromolar inhibitory activity
and good plasma stability. # 2002 Elsevier Science Ltd. All rights reserved.
Protein tyrosine phosphatase 1B (PTP1B) plays a role in
the negative regulation of insulin signaling and is
involved in the insulin resistance associated with Type 2
diabetes.1 Kennedy et al. have demonstrated that mice
lacking the PTP1B gene showed enhanced insulin sensi-
tivity.2 Treatment of these mice with insulin resulted in
prolonged and increased protein phosphorylation of the
insulin receptor in liver and muscle tissue, suggesting
that PTP1B is critical in the dephosphorylation of the
activated insulin receptor and that inhibition of this
enzyme would be an excellent strategy for the treatment
of Type 2 diabetes. Thus, PTP1B inhibitor could
potentially ameliorate insulin resistance and normalize
plasma glucose and insulin without inducing hypogly-
cemia, and could, therefore, be a major advance in the
treatment of Type 2 diabetes.3 Recently, small molecule
inhibitors of PTP 1B as well as peptide mimetics were
reported in papers and patents.4,5
We now report the synthesis of 1,2-naphthoquinone
derivatives by various synthetic methods and their
structure–activity relationship (SAR) study as a PTP1B
inhibitor.
A series of 1,2-naphthoquinone derivatives was synthe-
sized according to the synthetic Schemes 1–12. First, the
preparation of 1,2-naphthoquinone with substitutents at
R4 position was carried out as outlined in Schemes 1–6.
In the course of the search for protein tyrosine phos-
phatase inhibitor through HTS (high throughput
screening) using chemical library of Korea Chemical
Bank, 1,2-naphthoquinone skeleton was discovered as a
hit toward PTP1B inhibitor.
*Corresponding author. Tel.: +82-42-860-7070; fax: +82-42-860-
7160; e-mail: jkchoi@krict.re.kr
yAuthors contributed equally.
Scheme 1. (a) NaN3, AcOH, 40 ꢀC; (b) HNR0R00, K2CO3, H2O, room
temperature.
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00331-1

1942
J. H. Ahn et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1941–1946
.
Scheme 2. (a) ROH, CeCl3 7H2O, NaIO3.
Scheme 7. (a) Bromopentane, K2CO3, acetone, reflux or methyl 2-
hydroxy-3-phenylpropionate, DEAD, PPh3, benzene, room tempera-
ture; (b) (PhSeO)2O, THF, 50 ꢀC; (c) SeO2, AcOH, 60 ꢀC; (d)
Pd(OAc)2, benzene, AcOH, reflux or indole, CeCl3 7H2O, NaIO3, t-
BuOH, 40 ꢀC.
Scheme 3. (a) Pd(OAc)2, acetic acid, arene, reflux.
Scheme 8. (a) Benzyl chloroformate or ethyl chloroformate, Na2CO3,
THF/H2O, 0ꢀC ! room temperature; (b) (PhSeO)2O, THF, 50 ꢀC; (c)
Pd(OAc)2, benzene, AcOH, reflux or indole, CeCl3 7H2O, NaIO3, t-
BuOH, 40 ꢀC.
ꢀ
.
Scheme 4. (a) Indole derivatives, CeCl3 7H2O, NaIO3, t-BuOH, 40 C.
Scheme 9. (a) Methyl acrylate, Pd(OAc)2, n-Bu4NCl, KOAc, DMF,
150 ꢀC; (b) 10% Pd/C, H2, methanol, room temperature; (c)
(PhSeO)2O, THF, 50 ꢀC; (d) Pd(OAc)2, benzene, AcOH, reflux or
indole, CeCl3 7H2O, NaIO3, t-BuOH, 40 ꢀC.
Scheme 5. (a) Copper(I) cyanide, alkyl or aryl Grignard reagents, À78
! À20 ꢀC, THF.
Scheme 6. (a) Benzyl or cyclohexylmagnesium halide, Ni(dppp)Cl2,
ether, reflux; (b) BBr3, CH2Cl2, À78 ꢀC; (c) benzene seleninic anhy-
dride, THF, 50 ꢀC.
Scheme 10. (a) BnBr, K2CO3, acetone, reflux; (b) LiAlH4, THF, 0 ꢀC,
(c) MnO2, dioxane, room temperature; (d) PPh3¼CHCO2R, THF; (e)
NaOH, THF/H2O; (f) Et2NH, HOBt, EDCI; (g) 10% Pd/C, H2,
methanol, room temperature; (h) (PhSeO)2O, THF, 50 ꢀC; (i)
Pd(OAc)2, benzene, AcOH, reflux or indole, CeCl3 7H2O, NaIO3, t-
BuOH, 40 ꢀC.
Commercially available 1,2-naphthoquinone was trea-
ted with sodium azide in glacial acetic acid to afford 4-
amino-1,2-naphthoquinone (1).6 1,2-Naphthoquinone-
4-sulfonic acid sodium salt (from Aldrich, 6) reacted
with alkyl or aryl amines in the presence of K2CO3 to
produce the corresponding 4-alkyl or arylamino sub-
stituted-1,2-naphthoquinones (2 and 3). Introduction of
alkoxy group at R4 position was achieved by Takuwa
procedure using cerium chloride and sodium iodate in
alcohol to give the corresponding compounds (4–5)
(Scheme 2).7
The 1,2-naphthoquinones with aryl substituent at R4
position (7–18) were prepared by literature modification
(Scheme 3) using Pd(OAc)2 in arene and acetic acid
under the reflux condition.8
Another aryl substitution at R4-position with indole was
presented according to Scheme 4. 1,2-Naphthoquinone

J. H. Ahn et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1941–1946
1943
Scheme 11. (a) Ethyl p-bromobenzoate, Pd(OAc)2, n-Bu4NCl, KOAc,
DMF, 150 ꢀC; (b) 10% Pd/C, H2, methanol, room temperature; (c)
(PhSeO)2O, THF, 50 ꢀC; (d) Pd(OAc)2, benzene, AcOH, reflux.
Scheme 14. (a) Trifluoromethanesulfonic anhydride, pyridine,
CH2Cl2, 0 ꢀC ! room temperature; (b) methyl acrylate, Pd(OAc)2,
n-Bu4NCl, NaHCO3, DMF, 120 ꢀC; (c) 10%-Pd/C, H2, EtOH, room
temperature; (d) (PhSeO)2O, THF, 50 ꢀC; (e) indole, CeCl3 7H2O,
NaIO3, t-BuOH, 40 ꢀC.
Scheme 12. (a) (4-Bromophenoxy)-tert-butyldimethylsilane, n-BuLi,
THF, 0 ꢀC then THF, À20 ! 0 ꢀC, THF; (b) Et3SiH/TFA, CH2Cl2,
0 ꢀC; (c) TBAF, THF, 0 ꢀC; (d) BrCH2CO2But, K2CO3, KI, acetone,
reflux; (e) 10%-Pd/C, H2, EtOH, room temperature; (f) (PhSeO)2O,
THF, 50 ꢀC; (g) Pd(OAc)2, benzene, AcOH, reflux or indole, CeCl3
7H2O, NaIO3, t-BuOH, 40 ꢀC; (h) TFA, CH2Cl2, 0 ꢀC.
Alkylation of naphthalenediol (32) produced the mono
substituted compound (33), which upon treatment with
benzene seleninic anhydride11 afforded 1,2-naphthoqui-
none (34). Substitution of 1,2-naphthoquinone at R4
position with benzene8 or indole9 produced 4-aryl-1,2-
naphthoquinone with alkoxy group (36). Also methoxy
substituted 1,2-naphthoquinone could be prepared from
the corresponding tetralone (35) by SeO2 oxidation.12
The alkoxycarbonylamino-linked 1,2-naphthoquinones
were prepared by Scheme 8. Amino-2-naphthol (37)
reacted with benzyl or ethyl chlorofomate to give the
corresponding carbamates (38), followed by oxidation
and substitution (39) in a similar manner to Scheme 7.
The carbon-linked 1,2-naphthoquinones were achieved
by various synthetic routes. Bromonaphthylbenzyl ether
(40) was treated with ethyl acrylate and Pd(OAc)2 in
DMF to give a,b-unsaturated ester. Hydrogenation
using Pd/C under H2 atmosphere furnished 41, and
which was converted to 42 according to same oxidation
and R4 substitution procedure to Scheme 7.
Scheme 13. (a) Br2, AcOH, 0 ꢀC ! reflux; (b) Sn, 12 N HCl, AcOH,
reflux; (c) BnBr, K2CO3, acetone reflux; (d) LiAlH4, THF, 0 ꢀC, (e)
MnO2, dioxane, room temperature; (f) PPh3¼CHCO2R, THF; (g)
methyl acrylate, Pd(OAc)2, n-Bu4NCl, KOAc, DMF, 150 ꢀC; (h) 10%-
Pd/C, H2, EtOH, room temperature; (i) (PhSeO)2O, THF, 50 ꢀC; (j)
Pd(OAc)2, benzene, AcOH, reflux.
reacted with indole or indole derivatives in the presence
.
of CeCl3 7H2O and NaIO3 to afford 4-(indol-3-yl)-1,2-
naphthoquinones (entries 19–23).9
Commercially available 3-hydroxy-2-naphthoic acid
(43) was benzylated, and reduced by lithium aluminum
hydride to produce alcohol, followed by oxidation
(MnO2) to afford benzyloxynaphtylaldehyde (44).
A methodology to introduce alkyl or aryl group at R4
position from 1,2-naphthoquinone using Grignard
reagent with copper cyanide was attempted as shown in
Scheme 5.10
Introduction
of
a,b-unsaturated
ester
using
PPh3¼CHCO2R gave 45.
Compound 45 was hydrogenated by Pd/C under H2 gas
to produce 47, followed by oxidation and aryl substitu-
tion to afford the corresponding 1,2-naphthoquinones
(48). In Scheme 11, vinyl naphthylether (49) was cou-
pled with ethyl 4-bromobenzoate in the presence of
Pd(OAc)2 to give 50, which was converted to 51
according to Scheme 7.
Cyclohexyl or benzyl group at R4 could be obtained by
three-step synthesis from 1-iodo-4-methoxynaphthalene
(Scheme 6). 1-Iodo-4-methoxynaphthalene was coupled
with benzyl or cyclohexyl Grignard reagents in the pre-
sence of Ni(dppp)Cl2 in ether under the reflux condition
to produce the coupling product, followed by de-
methylation using BBr3, and oxidation with benzene
seleninic anhydride to afford the desired compounds (24
and 25).
Treatment of t-butyldimethylsilyl protected 4-bromo-
phenol with n-butyllithium followed by the addition of
aldehyde (44) furnished the corresponding alcohol (52).
Reduction of 52 with triethylsilane/trifluroacetic acid
and desilylation with tetrabutylammonium fluoride
afforded 53, followed by alkylation using t-butyl bro-
moacetate, deprotection of benzyl group, and then
converted to the final product 55.
4-Aryl-1,2-naphthoquinone derivatives with sub-
stituents at R3, R6, R7, or/and R8 were prepared
according to the synthetic Schemes 7–14. First, alkoxy-
linked 4-aryl-1,2-naphthoquinones were prepared by
Scheme 7.

1944
J. H. Ahn et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1941–1946
Tri-substituted 1,2-naphthoquinones were prepared
according to Schemes 13 and 14.
cence of the product, fluorescein monophosphate (FMT)
at 485nm (excitation) and 538 nm (emission).
3-Hydroxy-2-naphthoic acid (43) was brominated by
bromine and benzylated to produce 56. Compound 56
was reduced by lithium aluminum hydride to produce
alcohol, followed by oxidation (MnO2) afforded benzyl-
oxynaphtylaldehyde. Introduction of a,b-unsaturated
ester with PPh3¼CHCO2R gave 57. Introduction of
another a,b-unsaturated ester with methyl acrylate and
Pd(OAc)2 gave 58. Compound 58 was hydrogenated by
Pd/C under H2 gas, followed by oxidation and aryl
substitution produced 59. Compound 6013 reacted with
TfO2 to give 61. Coupling of 61 with methyl acrylate in
the presence of Pd(OAc)2 furnished di-unstaturated
ester (62), which was further converted to final com-
pound 63 according to Scheme 13.
1,2-Naphthoquinone was identified as a hit through
HTS (high throughput screening) with IC50 of 1.64 mM.
Since this compound had a unique skeleton and showed
a good in vitro activity against PTP1B, we used this
compound as a starting point with the aim of making a
potent and selective PTP1B inhibitor. Interestingly, 1,2-
naphthoquinone structures have been reported to show
inhibitory activity against phosphatases such as CD45,
Cdc25B.14,15 First, we decided to introduce substituents
at R4 position of 1,2-naphthoquinone to decrease
structural instability owing to Michael type nucleophilic
addition. The IC50 values are summarized in Table 1.
Introduction of amino, alkyl or aryl amino groups at
the R4-position (1–3) showed a decrease of the in vitro
activity compared with 1,2-naphthoquinone. Also sub-
stitutions of alkoxy group at R4 position were detri-
mental to the inhibitory activity (4 and 5). Whereas, aryl
substitution at R4 exhibited enhanced potency, 4-
phenyl-1,2-naphthoquinone (7) is the first of our com-
pound to break the micromolar barrier with IC50 value
of 0.86 mM and also showed better chemical and plasma
stability (data not shown, determined by HPLC) than
1,2-naphthoquinone.
The test compounds were evaluated for their in vitro
inhibitory activity against recombinant human PTP1B
using fluorescein diphosphate (FDP) as the substrate.
Enzyme activity was assayed by measuring the fluores-
Table 1. Inhibitory activity of 1,2-naphthoquinone derivatives
against PTP1B
Chloro or methoxy substituted phenyl analogues (8 and
9) were weaker than unsubstituted 4-phenyl-1,2-naph-
thoquinone (7). 2,5-Difluorophenyl analogue (10)
showed a good inhibitory activity (0.50 mM). Various
ester analogues of phenyl group (11–13) exhibited IC50
values in the range of 1.07–2.15 mM. Compound 14 was
another submicromolar inhibitor of PTP1B with an
IC50 value of 0.44 mM. Further aryl modification at R4
included the introduction of indole and its derivatives.
Indole (19) at R4 position demonstrated comparable
potency with 4-phenyl-1,2-naphthoquinone (7). Acid
substituted indoles (20 and 21) were less active than 19.
Masking of NH group (22) resulted in the loss of the in
vitro activity. Introduction of alkyl groups at R4 posi-
tion was another possibility to increase inhibitory
activity. Using the methodology through the reaction of
1,2-naphthoquinone with Grignard reagent in the pre-
sence of copper cyanide, several aryl or alkyl substituted
compounds were presented. Among them, cyclohexyl
analogue 24 was the best compound of this series with
an IC50 value of 0.32 mM. Other alkyl substituents at R4
position showed only weak activities (26–31).
Compd
R4 Substituents
IC50, mMa
1
2
3
4
5
6
7
8
–NH2
–N(CH3)C6H5
–N(CH2)4
24.59
34.88
nab
–OCH3
29.11
36.47
5.29
0.86
5.05
5.24
0.50
1.54
2.15
1.07
0.44
1.60
5. 73
1.17
2.15
1.13
3.00
4.56
na
–OCH2CH2CH2OH
–SO3Na
C6H5
–C6H5–2,5-Cl2
d
9
–C6H5OCH3
–C6H3–2,5-F2
–C6H4COOCH3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
d
–C6H4–2-OCH2CO2Et
–C6H4–4-OCH2CO2Et
–C6H4–4-OH
–C6H4–2-OH
–C6H2-3,5-di-t-butyl-4-OH—
C6H4-2-NO2
–1-Naphthyl
–3-Indole
–3-Indole-5-carboxylic acid
–3-Indole-6-carboxylic acid
–3-Indole-1,2–(CH3)2
–3-Indole-2–C6H5
–Cyclohexyl
na
0.32c
1.42c
3.30
4.20
5.40
10.13
na
Table 2. Selectivity of 1,2-naphthoquinone derivatives against several
phosphatasesa,b
–Benzyl
–(CH2)5CH3
–Cyclopentyl
–Biphenyl
Entry PTP1B
CD45LAR
Yop
PP1
CdBc 25
IC50, mM IC50, mM IC50, mM IC50, mM IC50, mM IC50, mM
–Isopropyl
–Butyl
–Decyl
Sodium vanadate16
7
0.86
1.54
1.13
0.32
0.84
1.65
3.07
3.27
2.49
7.09
10.2
8.99
21.07 8.37
11.97 Not tested
9.52
2.13
1.95
3.00
na
8.05
11
19
24
25.61
17.88
3.19
8.06
aIC50 values were determined from direct regression curve analysis.
bna, not active.
cThe compound was obtained by Scheme 4 or Scheme 5.
dRegioisomers were not separated.
aAll phosphatases are human enzymes.
bIC50 values were determined from direct regression curve analysis.

J. H. Ahn et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1941–1946
Table 3. Inhibitory activity of 1,2-naphthoquinone derivatives against PTP 1Ba
1945
No
R3
R4
R6
R7
R8
IC50
36a
36b
36c
36d
36e
36f
39a
39b
39c
42a
42b
48a
48b
48c
51
–O(CH2)4CH3
–C6H5
–C6H5
–C6H5
–C6H5
–C6H5
Indole
–C6H5
–C6H5
–C6H5
–C6H5
Indole
–C6H5
Indole
–C6H5
–C6H5
–C6H5
Indole
–C6H5
Indole
–C6H5
Indole
2.69
nab
–O(CH2)4CH3
–O(CH2)4CH3
OMe
–OCH(Bn)–CO2CH3
–OCH(Bn)–CO2H
NHCO2Bn
0.92
2.04
2.54
2.07
2.25
1.34
0.65
0.33
0.92
0.43
0.27
0.61
1.01
1.48
0.65
1.54
1.01
0.68
0.94
7.85
NHCO2Bn
NHCO2Et
–(CH2)2CO2Me
–(CH2)2CO2Me
–(CH2)2CO2Et
–(CH2)2CO2Et
–(CH2)2CONEt2
–(CH2)2PhCO2Et
55a
55b
55c
55d
59
–CH2Ph–4-O–CH2CO2But
–CH2Ph–4-O-CH2CO2But
–CH2Ph–4-O-CH2CO2H
–CH2Ph–4-O-CH2CO2H
–(CH2)2CO2Me
–(CH2)2CO2Me
63
–(CH2)2CO2Me
–(CH2)2CO2Me
Sodium vanadate16
aIC50 values were determined from direct regression curve analysis.
bna, not active.
The protein tyrosine phosphatase domains of receptor
and nonreceptor PTPases are highly conserved with
ꢁ35% mean sequence identity between known phos-
phatase.17 Therefore, it is essential that PTP1B inhibi-
tors intended for chronic therapy demonstrate a high
level of selectivity. The selectivity of several compounds
was evaluated in vitro against several phosphatases as
shown in Table 2. Compound 24 demonstrated 10- to
60-fold selectivity against the tested phosphatases.
Propionate analogue at R3 with phenyl at R4 (48a) also
exhibited a good activity similar to 42a. During the
synthesis of 4-aryl-1,2-naphthoqinones with carbon-
linked substituent at diverse position, 3-substituted-4-
aryl-1,2-naphthoquinone was more stable in plasma
than other 4-aryl-1,2-naphthoquinone with substituent
at R6, R7 or R8 as well as 4-aryl-1,2-naphthoquinone
(95% of the initially incorporated 3,4-disubstituted-1,2-
naphthoquinone was remained in plasma after 1 h,
determined by HPLC), so we focused on the synthesis
of 1,2-naphthoquinone with substituents at R3 and R4
to find out the candidate of showing good in vivo sta-
bility and efficacy. Compound 48b also showed a sub-
micromolar in vitro activity (0.27 mM). Propionamide
analogue (48c) was weaker than ester (48a or 48b). Sev-
eral other derivatives (51–55) were suggested and
inhibited PTP1B with in vitro activities with the range
of 0.6–1.5 mM.
Our initial assessment indicated that 1,2-naphthoqui-
none derivatives with substituent at R4 position showed
better inhibitory activity and stability than 1,2-naph-
thoquinone, so we further modified this structure (4-
substituted-1,2-naphthoquinone) by more substitution
at R3, R6, R7 and/or R8. Although cyclohexyl showed
most active in vitro inhibitory activity and selectivity as
the R4-substituent, we used phenyl or indolyl group as
the R4-substituents due to synthetic convenience. IC50
values are summarized in Table 3. Alkoxy-linked 4-aryl-
1,2-naphthoquinones (36a–f) showed moderate or no
inhibitory activity against PTP1B. Amino-linked 1,2-
naphthoquinones (39a–c) exhibited inhibitory activity
with the range of 0.64–2.25 mM. Compound 39a and 39b
showed similar activities to alkoxy-linked 1,2-naphtho-
quinones. While, compound 39c (0.65 mM) resulted in 2-
fold better than 39b. Carbon-linked 4-aryl-1,2-naphtho-
quinones were found to be more potent than alkoxy or
amino-linked 1,2-quinones. Introduction of propionate
at R6 with phenyl at R4 (42a) resulted in an increase of
the in vitro activity (0.33 mM), while compound 42b
with indole at R4 resulted in a 3-fold loss of activity.
Furthermore, 3-propionate-4-aryl-1,2-naphthoquinones
with substituent at R6 or R7 (59 and 63) were synthe-
sized and showed nanomolar range in vitro activity
(0.68 and 0.94 mM, respectively). As a proof-of-concept,
the compounds were also evaluated in vivo for their
ability to reduce plasma glucose levels in the ob/ob mice.
Compound 55b was most active at an oral dose of
25mg/kg/day for 5days. More robust in vivo tests, such
as biological stability, absorption and metabolism, are
required for confirmation of the activity and elucidation
of biological mechanism. Also modeling and X-ray co-
crystal studies with PTP1B and inhibitor are in progress
to understand how to increase the biological response.

1946
J. H. Ahn et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1941–1946
In conclusion, a new series of 1,2-naphthoquinone deri-
vatives was synthesized and evaluated for their ability to
inhibit protein tyrosine phosphatase 1B. The 1,2-naph-
thoquinone derivatives with nitrogen or oxygen sub-
stituent at R4 position showed weak in vitro activities.
Aryls such as phenyl or indole derivatives showed better
biological activity and stability than 1,2-naphthoqui-
none. The selectivity of several compounds was eval-
uated, and compound 24 demonstrated 10- to 60-fold
selectivity against the tested phosphatase. Also, several
4-aryl-1,2-naphthoquinone derivatives with substituents
at R3, R6, R7, and/or R8 showed submicromolar inhib-
itory activity and good plasma stability. Compound 55b
was active in vivo in ob/ob mice.
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Acknowledgements
The authors appreciate the financial support by Minis-
try of Science and Technology of Korea and Bioneer
Corporation.
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