4458 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15
Letters
A. Differentiation of CD4+ T cells to Th1 cells requires MAP kinase
JNK2. Immunity 1998, 9, 575-585. (c) Sabapathy, K.; Hu, Y.;
Kallunki, T.; Schreiber, M.; David, J. P.; Jochum, W.; Wagner, E.
F.; Karin, M. JNK2 is required for efficient T-cell activation and
apoptosis but not for normal lymphocyte development. Curr. Biol.
1999, 9, 116-125.
synthesis, and biological activity of novel, potent, and selective
(benzoylaminomethyl)thiophene sulfonamide inhibitors of c-Jun-N-
terminal kinase. J. Med. Chem. 2004, 47, 6921-6934. (d) Manning,
A. M.; Davis, R. J. Targeting JNK for therapeutic benefit: from junk
to gold? Nat. ReV. Drug DiscoVery 2003, 2, 554-565.
(14) Middleton, W. J. U.S. Patent 2,790,806, 1957 (E. I. du Pont de
Nemours and Co.). Metzger, R.; Oberdorfer, J.; Schwager, C.;
Thielecke, W.; Boldt, P. Einstufensynthese von 2,4-bis(sec-alkyl-
amino)-6-halogen-3-pyridincarbonitrilen (Synthesis of 2,4-bis(sec-
alkylamino)-6-halogen-3-pyridincarbonitriles). Liebigs Ann. Chem.
1980, 946-953.
(15) Junek, H.; Uray, G.; Kotzent, A. Isomere diamino-alkoxy-pyridin-
carbonitrilesihre trennung und verwendung als kupplungskompo-
nenten (Diaminoalkoxypyridincarbonitrile isomerssits separation and
use as components). Monatsh. Chem. 1983, 114, 973-982.
(16) Szczepankiewicz, B. G.; Kosogof, C.; Nelson, L. T. J.; Liu, G.; Liu,
B.; Zhao, H.; Serby, M. D.; Xin, Z.; Liu, M.; Gum, R. J.; Haasch,
D. L.; Wang, S.; Johnson, E. J.; Lubben, T. H.; Stashko, M. A.;
Olejniczak, E. T.; Sun, C.; Dorwin, S. A.; Haskins, K.; Abad-
Zapatero, C.; Fry, E. H.; Hutchins, C. W.; Rondinone, C.; Trevillyan,
J. M. Aminopyridine-based JNK inhibitors with cellular activity and
minimal cross-kinase activity. J. Med. Chem. 2006, 49, 3563-3580.
ATF-2 was the phosphorylation substrate, and 5 µM ATP was used
in the JNK enzymatic assay. HepG2 human hepatoma cells were
used in the cellular assay.
(17) Mittelbach, M.; Junek, H. Syntheses with nitriles. LXXIV. 3-Amino-
4,4-dicyano-3-butenoate, a synthetically useful dimer from malono-
nitrile and cyanoacetate. Liebigs Ann. Chem. 1986, 3, 533-544.
(18) Kingsbury, W. D.; Pendrak, I.; Leber, J. D.; Boehm, J. C.; Mallet,
B.; Sarau, H. M.; Foley, J. J.; Schmidt, D. B.; Daines, R. A. Synthesis
of structural analogues of leukotriene B4 and their receptor binding
activity. J. Med. Chem. 1993, 36, 3308-3320.
(19) Fanta, P. E.; Stein, R. A. The condensation of sodium nitromalonal-
dehyde with cyanoacetamide. J. Am. Chem. Soc. 1955, 77, 1045-
1046.
(4) Yang, D. D.; Kuan, C. Y.; Whitmarsh, A. J.; Rincon, M.; Zheng, T.
S.; Davis, R. J.; Rakic, P.; Flavell, R. A. Absence of excitotoxicity-
induced apoptosis in the hippocampus of mice lacking the Jnk3 gene.
Nature 1997, 389, 865-870.
(5) Wellen, K. E.; Hotamisligil, G. S. Inflammation, stress, and diabetes.
J. Clin. InVest. 2005, 115, 1111-1119.
(6) (a) Kershaw, E. E.; Flier, J. S. Adipose tissue as an endocrine organ.
J. Clin. Endocrinol. Metab. 2004, 89, 2548-2556. (b) Lazar, M. A.
How obesity causes diabetes: not a tall tale. Science 2005, 307, 373-
375.
(7) (a) Shin, E. A.; Kim, K. H.; Han, S. I.; Ha, K. S.; Kim, J. H.; Kang,
K. I.; Kim, H. D.; Kang, H. S. Arachidonic acid induces the activation
of the stress-activated protein kinase, membrane ruffling and H2O2
production via a small GTPase Rac1. FEBS Lett.1999, 452, 355-
359. (b) Rizzo, M. T.; Leaver, A. H.; Yu, W. M.; Kovacs, R. J.
Arachidonic acid induces mobilization of calcium stores and c-Jun
gene expression: evidence that intracellular calcium release is
associated with c-Jun activation. Prostaglandins, Leukotrienes Essent.
Fatty Acids, 1999, 60, 187-198. (c) Kyriakis, J. M.; Avruch, J.
Sounding the alarm: protein kinase cascades activated by stress and
inflammation. J. Biol. Chem. 1996, 271, 24313-24316.
(8) Aguirre, V.; Uchida, T.; Yenush, L.; Davis, R. J.; White, M. F. The
c-Jun NH2-terminal kinase promotes insulin resistance during as-
sociation with insulin receptor substrate-1 and phosphorylation of
Ser307. J. Biol. Chem. 2000, 275, 9047-9054.
(9) Aguirre, V.; Werner, E. D.; Giraud, J.; Lee, Y.; Shoelson, S. E.;
White, M. F. Phosphorylation of Ser307 in insulin receptor substrate-1
blocks interactions with the insulin receptor and inhibits insulin action.
J. Biol. Chem. 2002, 277, 1531-1537.
(10) Hirosumi, J.; Tuncman, G.; Chang, L.; Go¨rgu¨n, C. Z.; Uysal, K. T.;
Maeda, K.; Karin, M.; Hotamisligil, G. S. A central role for JNK in
obesity and insulin resistance. Nature 2002, 420, 333-336.
(11) Kaneto, H.; Nakatani, Y.; Miyatsuka, T.; Kawamori, D.; Matsuoka,
T.; Matsuhisa, M.; Kajimoto, Y.; Ichijo, H.; Yamasaki, Y.; Hori, M.
Possible novel therapy for diabetes with cell-permeable JNK-
inhibitory peptide. Nat. Med. 2004, 10, 1128-1132.
(20) Sakamoto, M.; Sano, T.; Fujita, S.; Ando, M.; Yamaguchi, K.; Mino,
T.; Fujita, T. Regioselective photocycloaddition of pyridine deriva-
tives to electron-rich alkenes. J. Org. Chem. 2003, 68, 1447-1450.
(21) Kosaku, H.; Kitade, Y.; Senda, S.; Halat, M. J.; Watanabe, K. A.;
Fox, J. J. Pyrimidines. 17. Novel pyrimidine to pyridine transforma-
tion reaction. One-step synthesis of pyrido[2,3-d]pyrimidines. J. Org.
Chem. 1981, 46, 846-851.
(12) Bennett, B.; Satoh, Y.; Lewis, A. J. JNK: a new therapeutic target
for diabetes. Curr. Opin. Pharmacol. 2003, 3, 420-425.
(22) Andrews, P. R.; Craik, D. J.; Martin, J. L. Functional group
contributions to drug-receptor interactions. J. Med. Chem. 1984, 27,
1648-1657.
(13) (a) Gaillard, P.; Jeanclaude-Etter, I.; Ardissone, V.; Arkinstall, S.;
Cambet, Y.; Camps, M.; Chabert, C.; Church, D.; Cirillo, R.;
Gretener, D.; Halazy, S.; Nichols, A.; Szyndralewiez, C.; Vitte, P.
A.; Gotteland, J. P. Design and synthesis of the first generation of
novel potent, selective, and in vivo active (benzothiazol-2-yl)-
acetonitrile inhibitors of the c-Jun N-terminal kinase. J Med. Chem.
2005, 48, 4596-4607. (b) Stocks, M. J.; Barber, S.; Ford, R.; Leroux,
F.; St-Gallay, S.; Teague, S.; Xue, Y. Structure-driven HtL: design
and synthesis of novel aminoindazole inhibitors of c-Jun N-terminal
kinase activity. Bioorg. Med. Chem. Lett. 2005, 15, 3459-3462. (c)
Ruckle, T.; Biamonte, M.; Grippi-Vallotton, T.; Arkinstall, S.;
Cambet, Y.; Camps, M.; Chabert, C.; Church, D. J.; Halazy, S.; Jiang,
X.; Martinou, I.; Nichols, A.; Sauer, W.; Gotteland, J. P. Design,
(23) Kuntz, I. D.; Chen, K.; Sharp, K. A.; Kollman, P. A. The maximal
affinity of ligands. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 9997-
10002. An exception is biotin, which binds to avidin with a binding
energy of ∼19 kcal/mol.
(24) This modification provides a 2-fold increase in enzymatic potency
for some analogues with different substitution patterns in the phenyl
ring.
(25) The refined crystallographic coordinates have been deposited in the
experimental details, see ref 16.
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