5-Substituted isophthalamides as insulin receptor sensitizers

Article abstract of DOI:10.1016/j.bmcl.2008.05.031

A novel series of 5-substituted isophthalamides and their structure-activity relationship as insulin receptor sensitizers is discussed.

Full text of DOI:10.1016/j.bmcl.2008.05.031

Bioorganic & Medicinal Chemistry Letters 18 (2008) 3492–3494
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
5-Substituted isophthalamides as insulin receptor sensitizers
*
Louise Robinson, Sonia Bajjalieh, Nicholas Cairns, Robert T. Lum , Robert W. Macsata,
Vara Prasad Manchem, Sophia J. Park, Sandhya Rao, Steven R. Schow, Songyuan Shi, Wayne R. Spevak
Telik, Inc., 3165 Porter Drive., Palo Alto, CA 94304, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of 5-substituted isophthalamides and their structure–activity relationship as insulin recep-
tor sensitizers is discussed.
Received 17 March 2008
Revised 6 May 2008
Accepted 8 May 2008
Available online 15 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Diabetes
Insulin receptor
SAR
Insulin resistance
Type 2, or non-insulin dependent, diabetes mellitus occurs in an
estimated 6% of adults in the industrialized nations.1 It is charac-
terized by a deficiency in insulin secretion and an insensitivity of
target tissues to the actions of insulin (insulin resistance).2–4 Taken
together these two defects result in the inability of the body to
maintain glucose homeostasis leading to overt hyperglycemia.
The insulin receptor is a ligand-activated tyrosine protein
kinase. It is tetrameric consisting of two identical extracellular
a-subunits that bind the hormone and two transmembrane b-sub-
units possessing tyrosine kinase activity.4–7 On ligand binding
rapid autophosphorylation of several tyrosine residues on the
b-subunits occurs resulting in activation of the IR tyrosine kinase
toward exogenous substrates. A cascade of signaling events then
ensue, one of which results in the translocation of the glucose
transporter, GLUT4, to the cell surface leading to cellular uptake
of glucose.8 Several steps in this pathway including autophospho-
rylation of the IR tyrosine kinase in response to insulin binding
have been shown to be impaired in insulin-resistant tissue and
cells.8 Therefore, small molecules that enhance IR function would
be useful in the treatment of type 2 diabetes. Indeed, recently such
a molecule has been disclosed by researchers at Merck. The
quinone, L-783,281 (Fig. 1) is reported to be an orally active IR
activator showing antidiabetic action in two mouse models of type
2 diabetes.9,10
presence of insulin to exert any effect. In our primary screen, the
effect of test compounds on the insulin-stimulated glucose uptake
H
N
O
HO
OH
O
N
H
SO3H
L-783,281
N
HO3S
N
OH
N
OH
N
N
O
HO3S
N
H
N
H
SO3H
N
N
HO3S
TLK16998 (1)
Using our target-related affinity profiling (TRAP) technology,11
TLK 16998 (1) was discovered (Fig. 1). This compound acts as an
IR sensitizer in vitro and in vivo,12 however, it does require the
N
SO3H
* Corresponding author. Tel.: +1 6508457745.
E-mail address: rlum@telik.com (R.T. Lum).
Figure 1. Structures of L-783,281 and TLK 16998.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.05.031

L. Robinson et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3492–3494
3493
NaO3S
H
N
O
COCl
NaO3S
SO3Na
Aq. NaOH, dioxane
SO3H
H
N
H
N
ClOC
COCl
O
O
(2)
NH2
Scheme 1. Synthesis of trimesic acid triamide 2.
Table 1
in 3T3-L1 adipocytes was evaluated and EC50 values were calcu-
lated with respect to the activity of 100 nM insulin. In this assay
compound 1 had an EC50 of 90 lM.
Glucose uptake data for compounds 3–11
From a medicinal chemistry point of view, compound 1 is unat-
tractive as a lead structure: it possesses six sulfonic acid groups as
well as four azo linkages and has a molecular weight greater than
1200. We envisaged a simpler, but still fairly rigid, structure which
maintained some of the acidic groups of the parent compound.
Therefore, a series of nine symmetrical trimesic acid amides were
prepared by reaction of 1,3,5-benzenetricarbonyl trichloride with
aminonaphthalene-monosulfonic acids. The 5-aminonaphthalene-
2-sulfonic acid derived triamide 2 (Scheme 1) was the only com-
pound in this series to show activity. It was very weakly active,
having an EC50 value of 135 lM.
A more promising series arose from 5-substituted isophthala-
mides (Table 1). Again the 5-aminonaphthalene-2-sulfonic
acid-derived diamides were superior to other aminonaphthalene-
sulfonic acid isomers. Compounds in this series were prepared by
the route shown in Scheme 2. Briefly, starting from 5-nitroisoph-
thalic acid amidation was followed by reduction of the nitro group
with subsequent functionalization of the aniline.
R
X
HN
5
-
-O3S
SO3
4
3
H
1
H
N
N
2
O
O
a
Compound
X
R
EC50 (lM)
3
4
5
6
7
8
9
10
11
CO
CO
CO
CO
CO
CO
3-Cl
4-Cl
3-F
5.7b
72.8c
19.4d
78.5e
44.5f
NA
4-F
3-NO2
4-NO2
4-F
3-Cl
3-Cl
SO2
CONH
COCH2
NA
NA
NA
p-value is the probability associated with a Student’s t-test (two-tailed distribution,
For the derivatives containing a substituted phenylcarbonyla-
mino group at C-5, substituents meta to the linker were preferably
to those para to the linker as illustrated by the chloro pairs 3 and 4
(EC50s 5.7 lM and 72.8 lM, respectively). The meta fluoro deriva-
tive 5 also shows good activity whilst the meta nitro-substituted
compound 7 shows diminished activity. Replacement of the amide
linkage at C5 of the isophthalamide scaffold with either urea or sul-
fonamide linkers produced compounds that were inactive (9 and
10) as did addition of an extra carbon to that amide (11). N-Meth-
ylation of the isophthalamide functionality also produced a com-
pound devoid in activity (data not shown) indicating that this
functionality is necessary for activity.
two-sample unequal variance). NA, not active.
a
Values are means of three experiments. Average p-values.
0.02.
0.38.
0 0.04.
0.36.
0.08
b
c
d
e
f
Having established the C-5 amide linker as an essential
requirement (compare 3 and 6 with 9–11), we next investigated
the effect of various heterocyclic and extended aromatic
replacements for the meta chloro phenyl of compound
2
NO2
NH2
-O3S
SO3-
(i), (ii)
H
N
H
N
HO2C
CO2H
O
O
Ar3SO2Cl
Ar1COCl
Ar3
Ar1
Ar2NCO
O
S
HN
HN
O
O
NHAr2
O
H
N
H
N
H
N
H
N
HN
O
O
O
O
H
H
N
N
O
O
Scheme 2. Reagents: (i) a—SOCl2, pyridine; b—5-aminonaphthalene-2-sulfonic acid, pyridine; (ii) SnCl2, concd HCl.

3494
L. Robinson et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3492–3494
Table 2
(Table 2). All the aromatic heterocycles tried gave compounds
Glucose uptake data for compounds 3, 12–18
with no activity (15, 16, 17, and 18). However, the 2-naphthyl
derivative 12 showed excellent activity having an EC50 of
3.7 lM with the 1-naphthyl analog 13 exhibiting slightly dimin-
ished activity.
Finally, the need for two sulfonic acid groups was explored
(Table 3). Two asymmetric derivatives were prepared in which
the one sulfonic acid moiety was exchanged for either a proton
19 or a hydroxyl 20. Both derivatives are ten times less active
than the parent. The symmetrical derivative containing two car-
boxylic acids instead of two sulfonic acids was inactive. These
data suggest that at least one sulfonic acid group is a necessity
for activity but the presence of two such groups increases
potency.
In summary, a series of isophthalamides that enhance glu-
cose transport have been disclosed. Unlike L-783,281, the com-
pounds reported herein are inactive in the absence of insulin.
Of course, such insulin-dependent activity may offer unique
advantages in the control of hyperglycemia by modulation of
their effects as insulin levels change in response to physiologi-
cal stimuli.
R1
HN
O
O
SO3-
-O3S
H
N
H
N
O
R1
EC50 (lM)
a
Compound
3
12
13
14
15
16
17
18
3-Cl-phenyl
2-Naphthayl
1-Naphthyl
Cyclohexyl
2-Furyl
4-Pyridyl
3-Pyridyl
2-Quinoxyl
5.7b
3.7c
12.8d
NA
NA
NA
NA
NA
p-value is the probability associated with a Student’s t-test (two-tailed distribution,
two-sample unequal variance). NA, not active.
a
Values are means of three experiments. Average p-values.
0.02.
0.01.
0.41.
b
c
d
References and notes
1. Moller, D. E. Nature (London) 2001, 414, 821.
2. Bennet, P. H. In Diabetes Mellitus: A Fundamental and Clinical Text; LeRoith, D.,
Table 3
Taylor, S. I., Olefsky, J. M., Eds., 2nd ed.; Lippincott Wlliams
Philadelphia, 2000; pp 544–548.
& Wilkins:
Glucose uptake data for compounds 2, 19, and 20
3. Taylor, S. I. Cell 1999, 97, 9.
Cl
4. Kahn, C. R.; Shechter, Y. In Goodman and Gilman’s The the Pharmacological Basis
of Therapeutics; Goodman Gilman, A., Rall, T. W., Nies, A. S., Taylor, P., Eds., 8th
ed.; Pergamon: New York, 1990; pp 1468–1475.
5. Hubbard, S. R.; Wei, L.; Ellis, L.; Hendrickson, W. A. Nature (London) 1994, 372,
746.
6. Goldfine, I. D. Endocr. Rev. 1987, 8, 235.
HN
O
O
R2
-O3S
H
N
H
N
7. Acilli, D.; Nakae, J.; Flier, J. S. In Diabetes Mellitus: A Fundamental and Clinical
Text; LeRoith, D., Taylor, S. I., Olefsky, J. M., Eds., 2nd ed.; Lippincott Wlliams &
Wilkins: Philadelphia, 2000; pp 192–199.
8. Virkamaki, A.; Urki, K.; Kahn, C. R. J. Clin. Invest. 1999, 103, 931.
9. Zhang, B.; Salituro, G.; Szalkowski, D.; Li, Z.; Zhang, Y.; Royo, I.; Vilella, D.; Diez,
M. T.; Pelaez, F.; Ruby, C.; Kendall, R. L.; Mao, X.; Griffin, P.; Calaycay, J.; Zierath,
J. R.; Heck, J. V.; Smith, R. G.; Moller, D. E. Science (Washington, DC) 1999, 284,
974.
O
a
Compound
R2
EC50 (lM)
À
2
19
20
SO3
H
5.7b
66.5c
61.7d
10. Liu, K.; Xu, L.; Szalkowski, D.; Li, Z.; Ding, V.; Kwei, G.; Huskey, S.; Moller, D. E.;
Hwck, J. V.; Jones, A. B. J. Med. Chem. 2000, 43, 3447.
OH
11. Beroza, P.; Damodaran, K.; Lum, R. T. Curr. Top. Med. Chem. 2005, 5,
371.
p-value is the probability associated with a Student’s t-test (two-tailed distribution,
two-sample unequal variance). NA, not active.
12. Manchem, Vara Prasad; Goldfine, I. D.; Kohanski, R. A.; Cristibal, C. P.;
Lum, R. T.; Schow, S. R.; Shi, S.; Spevak, W. R.; Laborde, E.; Tovas, D.
K.; Villar, H. O.; Wick, M. M.; Kozlowski, M. R. Diabetes 2001, 50,
824.
a
Values are means of three experiments. Average p-values.
0.02.
0.23.
b
c
d
0.16.