Lead optimization of methionine aminopeptidase-2 (MetAP2) inhibitors containing sulfonamides of 5,6-disubstituted anthranilic acids

Article abstract of DOI:10.1016/j.bmcl.2007.02.062

A series of aryl sulfonamides of 5,6-disubstituted anthranilic acids were identified as potent inhibitors of methionine aminopeptidase-2 (MetAP2). Small alkyl groups and 3-furyl were tolerated at the 5-position of anthranilic acid, while -OCH₃, CH₃, and Cl were found optimal for the 6-position. Placement of 2-aminoethoxy group at the 6-position enabled interaction with the second Mn²⁺ but did not result in enhancement in potency. Introduction of a tertiary amino moiety at the ortho-position of the sulfonyl phenyl ring gave reduced protein binding and improved cellular activity, but led to lower oral bioavailability.

Full text of DOI:10.1016/j.bmcl.2007.02.062

Bioorganic & Medicinal Chemistry Letters 17 (2007) 2817–2822
Lead optimization of methionine aminopeptidase-2 (MetAP2)
inhibitors containing sulfonamides of 5,6-disubstituted
anthranilic acids
Gary T. Wang,* Robert A. Mantei, Megumi Kawai, Jason S. Tedrow, David M. Barnes,
Jieyi Wang, Qian Zhang, Pingping Lou, Lora A. Garcia, Jennifer Bouska, Melinda Yates,
Chang Park, Russell A. Judge, Richard Lesniewski, George S. Sheppard and Randy L. Bell
Cancer Research, Global Pharmaceutical Research & Development, Abbott Laboratories, Abbott Park, IL 60064, USA
Received 17 January 2007; revised 16 February 2007; accepted 22 February 2007
Available online 25 February 2007
Abstract—A series of aryl sulfonamides of 5,6-disubstituted anthranilic acids were identified as potent inhibitors of methionine ami-
nopeptidase-2 (MetAP2). Small alkyl groups and 3-furyl were tolerated at the 5-position of anthranilic acid, while –OCH3, CH3, and
Cl were found optimal for the 6-position. Placement of 2-aminoethoxy group at the 6-position enabled interaction with the second
Mn2+ but did not result in enhancement in potency. Introduction of a tertiary amino moiety at the ortho-position of the sulfonyl
phenyl ring gave reduced protein binding and improved cellular activity, but led to lower oral bioavailability.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The intracellular enzyme methionine aminopeptidase-2
(MetAP2) came into the focus as a potential anti-tumor
therapeutic target when it was identified as the molecu-
lar target of the anti-cancer natural product fumagilin
and its synthetic analog TNP-470.1–3 TNP-470 has
exhibited potent anti-tumor efficacy in a variety of ani-
mal xenograft models as well as in transgenic tumor
models and has shown varying degrees of efficacy
against several human cancers in clinical trials.4 Both
fumagilin and TNP-470 exert their anti-tumor effect pri-
marily through inhibition of endothelial cell prolifera-
tion, even though these molecules also inhibit the
proliferation of a subset of tumor cells.5,6 This anti-
angiogenic activity of fumagilin and TNP-470 has been
attributed to the irreversible inhibition of MetAP2.1–3
More recently, a rationally designed reversible inhibitor
of MetAP2 based on bestatin has also been reported to
have potent anti-angiogenic activity both in vitro and
in vivo, and potent anti-tumor efficacy in several animal
models, further supporting the validity of MetAP2 as an
anti-cancer target.7–9 Several other series of reversible
inhibitors of MetAP2 have also been reported.10,11 Bio-
chemically, MetAP2 is a metalloproteinase responsible
for the removal of the N-terminal initiator methionine
residue of nascent proteins. It is required for protein
co- and/or post-translational modifications, such as
NH2-terminal myristoylation, and for protein stabil-
ity.12–14 The active site of MetAP2 is believed to contain
two metal cations, either Co2+ or Mn2+, with Mn2+
being characterized as the physiologically relevant
cofactor.14
Recently, we have described a series of sulfonamides of
anthranilic acid as MetAP2 inhibitors.15–17 Starting
from a screening lead 1 (Fig. 1), initial lead optimization
led to the tetrahydronaphthyl sulfonamide 2 (Fig. 1),
which is a potent MetAP2 inhibitor but lacks cellular
activity and is highly protein bound. The X-ray crystal-
lographic structure of compound 2 complexed to
Br
O
S
O
O
S
O
N
N
H
H
O
OH
Cl
O
OH
2 (IC50=9 nM)
Keywords: Methionine aminopeptidase-2 (MetAP2) inhibitors; Sulfon-
amides of 5,6-disubstituted anthranilic acids.
1 (IC50=11,000 nM)
*
Figure 1.
Corresponding author. E-mail: gary.t.wang@abbott.com
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.02.062

2818
G. T. Wang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2817–2822
MetAP2 revealed that the carboxylate chelates one of
the two manganese ions and the rigid tetrahydronaph-
thyl moiety fits rather tightly into a hydrophobic pocket
of the active site.16 Consistent with this observation, in a
few limited examples with substitution on the cyclohexyl
ring of the tetrahydronaphthyl moiety, reduction in en-
zyme inhibition IC50 was observed.15 We reasoned that
breaking open the cyclohexyl ring to form 5,6-disubsti-
tuted anthranilic acid derivatives would offer more flex-
ibility and allow for fully optimized interaction with the
key hydrophobic binding pocket of the enzyme. This
added flexibility might also offer the potential to form
an interaction with the second manganese in the active
site. In this paper, we describe the results of this effort.
previously.14 We have reported previously that, for sul-
fonamides of 5-alkyl mono-substituted anthranilic acids,
an ethyl group at the 5-position such as in the reference
compound 9o is optimal.15 As shown in Table 1, this
trend holds for the current 5,6-disubstituted anthranilic
acid series: 5-alkyl lower (9a) or higher (9d, 9e) than
5-ethyl (9c) gave less potent MetAP2 inhibitors. In com-
parison with the reference compound 9o, adding a C6
methyl (9c), methoxy (9h) or chloro- (9n) results in
3- to 4-fold increase in MetAP2 inhibitory potency. Several
five-membered ring heteroaryls were also examined as
the C5-substituents (9i–m). Interestingly, 3-furyl was
found to give compounds equi-potent to the 5-ethyl
counterpart (9i vs 9h), whereas 2-furyl, 4-imidazolyl,
and 4-pyrazolyl all gave much less active compounds
(9k–m).
Synthesis of the required 5,6-disubstituted anthranilic
acid sulfonamides followed one of the general routes
shown in Scheme 1.17 Isatoic anhydrides 4 were prepared
from 6-substituted anthranilic acids 3 in high yield. Bro-
mination of 4 with NBS gave modest yields of compounds
5, which were converted to the anthranilic acid methyl
esters 6 by refluxing in MeOH. Suzuki coupling of 6 with
vinylboronic acidsorboronates, followedbyPd-catalyzed
hydrogenation, sulfonylation, and saponification, gave
the 5-alkyl compounds 9c–e, 9h, and 9n. Suzuki coupling
of 6 with heteroaryl boronic acids gave 11, which led to
compounds 9i–m upon sulfonylation and saponification.
The 5-hydroxymethyl compound 9f and 5-(1-hydroxyeth-
yl) compound 9g were obtained from the 5-vinyl com-
pound 10 using standard chemistry (Fig. 2).
X-ray crystallographic structures of 4-fluorophenyl sul-
fonamide of 5-ethyl-6-methyl-anthranilic acid 9c and
tetrahydronaphthyl sulfonamide 2 complexed with
MetAP2 (Fig. 1) indicated essentially identical binding
interactions between these two molecules. The X-ray
structure of 9c also revealed the possibility of reaching
to the second Mn2+ atom by extending the 6-methyl
group of 9c. We choose to explore this possibility by
extending the 6-methoxy group of 9h with the chemistry
shown in Scheme 2, with the results summarized in
Table 2.
Extending the 6-methoxy group of 9h to 6-ethoxy group
of 16a resulted in a modest loss of potency (from 10 to
40 nM), whereas further extending to 6-propoxy (as
2-fluorophenyl-sulfonamide) abolished the activity
The compounds were tested in MetAP2 inhibition
assays and cellular proliferation assays described
Br
Br
a
b
c
d
R1
H2N
HO
R1
HN
R1
HN
H2N
R1
CO2Me
O
O
O
O
O
O
O
6
3 (R1=Me, -OMe, -Cl)
5
4
R'
R'
R'
O O
e
f
S
Ar
N
H
R1
CO2H
R1
CO2Me
H2N
R1
CO2Me
H2N
9c-e, 9h, 9n
7
8
g
f
9f
9g
h
i
O O
S
9b
N
H
CO2Me
F
10
Ar'
O
Ar'
O O
S
j
f
6
Ar
N
(R1=-OMe)
H2N
O
H
CO2H
CO2Me
9i-m
11
Scheme 1. Reagents and conditions: (a) phosgene, NaOH, H2O, 90%; (b) NBS, DMF, DCM, 45%; (c) MeOH, reflux, 80%; (d) R0CH@CHB(OH)2,
Pd(PPh3)4, CsF, DME, MeOH, 150 ꢁC (lwave), 5 min, ꢀ80%; (e) H2, Pd/C, MeOH, 90%; (f) i—4-fluorophenyl sulfonyl chloride, pyridine, DCM,
90–95%; ii—LiOH (10·), dioxane, H2O, 160 ꢁC (lwave), 15 min, 40–70%; (g) 4-fluorophenyl sulfonyl chloride, pyridine, DCM, 90%; (h) i—OsO4,
NaIO4, dioxane, H2O; ii—NaBH4, EtOH; iii—LiOH (10·), dioxane, H2O, 160 ꢁC (lwave), 15 min; (i) i—OsO4, NaIO4, dioxane, H2O;
ii—CH3MgBr, THF; iii—LiOH (10·), dioxane, H2O, 160 ꢁC (lwave), 15 min; (j) Ar0B(OH)2, Pd(PPh3)4, CsF, DME, MeOH, 150 ꢁC (lwave), 5 min,
ꢀ80%.

G. T. Wang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2817–2822
2819
Figure 2. X-ray crystallographic structure of MetAP2 complexed with compound 2 (green), 9c (purple), and 17a (brown). The atomic coordinates
have been deposited with the Protein Data Bank (1YW8, 2EA2, 2EA4).
Table 1. Initial optimization of 5,6-disubstituted anthranilic acid sulfonamides
4
5 R2
3
X
O
S
O
6
R1
OH
2
N
1
H
F
O
Compound ID
X
R1
R2
Enzyme IC50 (lM)
Enzyme IC50 w/HSAa(lM)
HT-1080 prol. EC50 (lM)
9a
9b
9c
H
H
H
CH3–
CH3–
CH3–
CH3–
CH2@CH2–
CH3CH2–
0.078
0.060
0.016
4.2
4.0
0.76
4.9
9d
9e
H
H
CH3–
CH3–
0.15
1.3
12
OH
OH
9f
H
H
CH3–
CH3–
8.0
2.5
>100
>100
9g
9h
9i
H
H
CH3O–
CH3O–
CH3CH2–
0.011
0.008
1.7
1.1
1.4
3.8
O
O
O
9j
Br
Br
Br
CH3O–
CH3O–
CH3O–
0.02
1.0
20
11
9k
9l
>100
>100
H
N
36
N
N
9m
H
CH3O–
0.28
14
NH
9n
9o
H
H
Cl–
H
CH3CH2–
CH3CH2–
0.015
0.055
1.8
4.2
a MetAP2 inhibition activity in the presence of 40 mg/mL of human serum albumin (HSA).

2820
G. T. Wang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2817–2822
Br
Br
Br
a
c
b
5 (R1=-OMe)
R
HN
OH
H2N
OH
CO2Me
H2N
O
CO2Me
O
O
O
14a (R=Et)
12
13
14b (R= -CH2CH2NH-Boc)
14c (R= -CH2CO2-tBu)
Br
O
O O
S
O O
S
R
R
d
e
N
O
CO2H
N
H
H
CO2Me
F
F
15a-c
16a (R=Et)
16b (R= -CH2CH2NH-Boc)
16c (R= -CH2CO2-tBu)
f
17a
17b
f
Scheme 2. Reagents and conditions: (a) AlCl3, DCM, rt; (b) MeOH, reflux, 3 h, 80% for two steps; (c) EtI or Boc–NH–CH2CH2Br or
t
BrCH2CO2 Bu, Cs2CO3, DMF, 0 ꢁC, ꢀ90%; (d) 4-fluorophenylsulfonyl chloride, pyridine, DCM, 90–95%; (e) i—CH2@CHB(OBu)2, Pd(PPh3)4,
CsF, DME, MeOH, 150 ꢁC (lwave), 5 min, ꢀ80%; ii—H2, Pd/C, MeOH, ꢀ90%; iii—LiOH (10·), dioxane, H2O, 160 ꢁC (lwave), 15 min, 40–70%; (f)
80% TFA in DCM, rt, 3 h, ꢀ90%.
Table 2. Efforts to reach the second manganese ion via C6 substitution
cellular MetAP2, as well as the active MetAP2 present in
our assays, may lack a second active site metal.18
O
S
O
N
R
The MetAP2 inhibitory potency of most compounds in
Tables 1 and 2 showed a large reduction when 40 mg/mL
of human serum albumin (HSA) was included in the
enzyme assay (e.g., 48-fold, 154-fold, and 177-fold for
compounds 9c, 9h, and 9i, respectively). Additionally,
most of these compounds had poor cellular activity in
the HT-1080 proliferation assay. We have reported pre-
viously that introduction of tertiary amino functional-
ities at the ortho-position of the sulfonyl phenyl ring
significantly reduced protein binding and improved cel-
lular activity in related compounds.16 Thus, similar
structural modifications were made to the current series.
The requisite compounds were prepared following the
general procedure depicted in Scheme 3,16,17 and the
biological results are summarized in Table 3. These com-
pounds showed only 4- to 10-fold reduction in the IC50
in the enzymatic assay when 40 mg/mL of HSA was
present. In terms of cellular anti-proliferation activity,
compounds with the aminoalkyl moieties attached to
H
F
O
OH
Compound
ID
R
Enzyme
Enzyme
IC50 (lM) IC50 w/HSAa (lM)
9c
9h
–CH3
–OCH3
0.016
0.011
0.76
1.7
O
O
16a
17a
17b
0.038
0.046
5.8
40
0.12
>100
NH2
CO2H
O
a MetAP2 inhibition activity in the presence of 40 mg/mL of HSA.
completely (IC50 > 10 lM, data not shown in Table 2).
However, the 6-(2-aminoethoxy) compound 17a turned
out to be a MetAP2 inhibitor about equi-potent to
the 6-ethoxy compound 16a. The X-ray structure of
MetAP2 complexed to 17a revealed that the side-chain ami-
no group of 17a displaced a water molecule and indeed
was oriented to interact with the second Mn2+ (Fig. 1),
with the distance from the aminoethoxy nitrogen of
R2
R1
R2
R1
R'
NH
F
O O
S
O O
S
c
N
N
H
H
CO2H
CO2H
17a to the second Mn2+ being 2.5 A. In comparison,
˚
the distances from the two oxygen atoms of the carbox-
ylate to the first Mn2+ were 2.2 and 3.5 A, respectively,
˚
18
19d-f, 19h
R"
R2
R2
R1
for all three compounds in Figure 1. Thus, we were dis-
appointed to find that there was no gain in potency from
16a to 17a. One possible explanation for this result is
that the NH2–Mn2+ interaction is weak relative to the
interaction between this Mn2+ and the displaced water.
Another plausible explanation resides in the very recent
report of catalytically active monometalated bacterial
MetAP1,18 which suggests that the dimetalated MetAP2
observed in X-ray crystallographic structures might be a
crystallization artifact, while the relevant form of intra-
N
Br
O O
S
R'
O O
d
R1
CO2Me
S
N
N
H
H
CO2H
F
F
20
19g, 19i
Scheme 3. Reagents and conditions: (c) R0NH2 (8·), Et3N (5·),
acetonitrile, 90 ꢁC, 3 days, ꢀ50%; (d) i—Z-(2-diethylaminomethyl)-
vinyl tri-butyltin, (t-Bu3P)2Pd, Pd2(dba)3, toluene, 90 ꢁC, 50–80%;
ii—LiOH (10·), dioxane, H2O, 160 ꢁC (lwave), 15 min, 40–70%.

G. T. Wang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2817–2822
Table 3. Sulfonamides containing amino groups
2821
R2
R1
O
S
O
Ar
N
H
19
O
OH
Compound ID
Ar
R1
R2
Enzyme IC50 (lM)
No HSA
w/HSAa
HT-1080 prol.
EC50 (lM)
No HSA
w/HSAb
O
19a
19b
CH3CH2–
CH3CH2–
0.016
0.067
0.23
83
12
NH2
N
CH3–
0.555
N
O
19c
CH3CH2–
0.024
0.085
30
NH2
F
N
NH
NH
19d
19e
CH3O–
CH3O–
CH3CH2–
CH3CH2–
0.010
0.018
0.097
0.175
0.25
0.37
1.2
N
N
0.37
NH
N
19f
CH3O–
CH3O–
CH3CH2–
CH3CH2–
0.015
0.026
0.085
0.080
0.48
0.07
1.9
19g
0.15
F
F
NH
N
O
O
19h
19i
CH3O–
CH3O–
0.017
0.015
0.096
0.087
0.32
0.06
2.9
N
0.20
F
a Enzyme inhibition activity in the presence of 40 mg/mL of HSA.
b Anti-proliferative activity in the presence of 40 mg/mL of HSA.
the ortho-position of the sulfonyl phenyl ring via a nitro-
gen atom (19d–f, 19h) all showed EC50 < 0.5 lM. In par-
ticular, compounds with an amino-Z-alkenyl moiety
attached to the ortho-position of the sulfonyl phenyl ring
(19g and 19i) showed potent anti-proliferation activity
(0.07 and 0.06 lM, respectively), consistent with the ear-
lier report.16
group as in 19d, 19f, and 17a resulted in lower volume
of distribution, increased clearance, and much lower
oral bioavailability. The Z-alkenyl substituted 19g
had a larger volume of distribution relative to 19b
but very high clearance. As a result, its oral bioavail-
ability was also very low (16%).
In summary, we have identified a series of sulfonamides
of 5,6-disubstituted anthranilic acids as potent inhibitors
of MetAP2. The most potent compounds, 19g and 19i,
display potent MetAP2 inhibition (IC50 ꢀ 20 nM) and
anti-proliferation activity against HT-1080 cells
(EC50 ꢀ 60 nM).
The mouse pharmacokinetic data for selected com-
pounds are summarized in Table 4. The pyridyl sul-
fonamide 19b has
a relatively large volume of
distribution and low clearance and consequently good
oral bioavailability (86%). Installation of an amino

2822
G. T. Wang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2817–2822
Table 4. Mouse pharmacokinetics of selected compounds
Compound
IV (10 mg/kg)
CL (L/h kg)
PO (30 mg/kg)
ID
Structure
t1/2 (h)
Vd (L/kg)
AUC (mg h/mL)
19.8
Cmax (lM)
AUC (mg h/mL)
F (%)
O
O
N
N
S
19b
2.4
5.5
1.6
2.1
34
60.9
9.9
86
N
H
CO H
2
NH
O O
19d
19f
19g
0.3
0.3
0.2
0.8
2.0
10.8
4.3
5.9
0.9
0.1
31
13
16
S
N
O
H
CO H
2
N
NH
O O
5.0
1.7
S
N
O
H
CO H
2
N
O O
13.8
40.5
0.5
0.26
S
N
H
O
CO H
2
F
O O
S
NH
2
17a
0.3
1.1
3.0
8.6
2.4
9.8
38
N
O
H
CO H
2
F
Abbreviations: Vd, volume of distribution; CL, clearance; AUC, area under the curve; Cmax, maximum concentration; F, oral bioavailability.
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