J.-P. Wu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5547–5551
5551
W.; Strnad, J.; Qiu, Y.; Zusi, F. C. J. Biol. Chem. 2003, 278, 1450; (e) McIntyre, K.
W.; Shuster, D. J.; Gillooly, K. M.; Dambach, D. M.; Pattoli, M. A.; Lu, P.; Zhou, X.-
D.; Qiu, Y.; Zusi, F. C.; Burke, J. R. Arthritis Rheum. 2003, 48, 2652; (f) Baxter, A.;
Brough, S.; Cooper, A.; Floettmann, E.; Foster, S.; Harding, C.; Kettle, J.; McInally,
T.; Martin, C.; Mobbs, M.; Needham, M.; Newham, P.; Paine, S.; St-Gallay, S.;
Salter, S.; Unitt, J.; Xue, Y. Bioorg. Med. Chem. Lett. 2004, 14, 2817; (g) Castro, A.
C.; Dang, L. C.; Soucy, F.; Grenier, L.; Mazdiyasni, H.; Hottelet, M.; Parent, L.;
Pien, C.; Palombella, V.; Adams, J. Bioorg. Med. Chem. Lett. 2003, 13, 2419; (h)
Bonafoux, D.; Bonar, S.; Christine, L.; Clare, M.; Donnelly, A.; Guzova, J.; Nandini
Kishore, N.; Lennon, P.; Libby, A.; Mathialagan, S.; McGhee, W.; Rouw, S.;
Sommers, C.; Tollefson, M.; Tripp, C.; Richard Weier, R.; Wolfsona, S.; Min, Y.
Bioorg. Med. Chem. Lett. 2005, 15, 2870; (i) Christopher, J. A.; Avitabile, B. G.;
Bamborough, P.; Champigny, A. C.; Cutler, G. J.; Dyos, S. L.; Grace, K. G.; Kerns, J.
K.; Kitson, J. D.; Mellor, G. W.; Morey, J. V.; Morse, M. A.; O’Malley, C. F.; Patel, C.
B.; Probst, N.; Rumsey, W.; Smith, C.; Wilson, M. J. Bioorg. Med. Chem. Lett. 2007,
17, 3972; (j) Belema, M.; Bunker, A.; Nguyen, V. N.; Beaulieu, F.; Ouellet, C.; Qiu,
Y.; Zhang, Y.; Martel, A.; Burke, J.; McIntyre, K. W.; Pattoli, M. A.; Daloisio, C.;
Gillooly, K. M.; Clarke, W. J.; Brassil, P. J.; Zusi, F. C.; Vyas, D. M. Bioorg. Med.
Chem. Lett. 2007, 17, 4284.
kinases at 50% POC (percent of control) or less. For the tyrosine ki-
nase panel, with the exception that compound 46 inhibits PDGFR
at 0.3 M (IC50), no other kinases were inhibited at IC50’s below
M. Overall, these compounds demonstrated excellent kinase
a
l
7
l
selectivity profiles (Table 5, columns 3–5).
Another issue relates to the mechanism by which these com-
pounds inhibit TNF
nisms other than interference with the NF-
mechanistic verification, compounds 44–46 and 48 were tested
in a HeLa cell NF- B reporter gene assay, a cellular assay specific
for the NF-
B pathway.12a In this assay, compounds 44–46 and
48 gave IC50’s in the low micromolar range, indicating that they in-
deed interfere with the NF- B pathway (Table 5, column 6).
a
production, which could be due to mecha-
jB pathway. As a
j
j
j
To summarize, we have identified a series of potent IKKb inhib-
itors from the thienopyridine structural class. These compounds
inhibit IKKb in the low nanomolar range, suppress LPS-induced
5. Morwick, T.; Berry, A.; Brickwood, J.; Cardozo, M.; Katrina Catron, K.; DeTuri,
M.; Hrapchak, M.; Jacober, S.; Jakes, S.; Kaplita, P.; Ksiazek, J.; Liuzzi, M.;
Magolda, R.; Marshall, D.; McNeil, A.; Prokopowicz, A., III; Sarko, C.; Scouten, E.;
Sledziona, C.; Watrous, J.; Wu, J.-P.; Cywin, C. J. Med. Chem. 2006, 49, 2898.
6. Mittelbach, M. et al Arch. Pharm. (Weinheim Ger.) 1985, 318, 481.
7. Dimethylthiovinylketone 5 was prepared according to a literature procedure.
See Spitzner, R.; Menzel, M.; Schroth, W. Synthesis 1982, 3, 206–210.
8. Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979.
TNF-
a
production in human whole blood and in mice (oral dosing),
and a range of ser-
and have good selectivity profiles against IKK
a
ine/threonine and tyrosine kinases. In addition, they demonstrate
activity in a cell based reporter gene assay dependent upon signal-
ing through NF-jB, showing that these compounds directly inter-
fere with the target pathway.
9. (a) Ratemi, E. S.; Namdev, N.; Gibson, M. S. J. Heterocycl. Chem. 1993, 30, 1513;
(b) Sharaf, S. M.; El-Sadany, S. K.; Hamed, E. A.; Youssef, A.-H. A. Can J. Chem.
1991, 69, 1445.
10. The two enantiomers 57 and 58 were obtained by chiral HPLC resolution of the
racemic material, each >98% ee. The absolute stereochemistry for each
compound was not determined.
11. An IKKb homology model was generated using the MODELLER program with
five kinase X-ray structures as templates, including the structures of CDK2,
PHK, LCK, JNK, and CPK (cAMP dependent protein kinase).
References and notes
1. (a) Barnes, P.; Karin, M. N. Engl. J. Med. 1997, 336, 1066; (b) Karin, M.; Cao, Y.;
Greten, F. R.; Li, Z. W. Nat. Rev. Cancer 2002, 2, 301; (c) Barkett, M.; Gilmore, T.
D. Oncogene 1999, 18, 6910; (d) Baeuerle, P. A.; Baltimore, D. Cell 1996, 87, 13.
2. Karin, M. Oncogene 1999, 18, 6867.
3. A selection of patents and patent applications claiming IKK inhibitors is listed
below: WO0158890(A1); US20020107252; WO03010163; WO03010158;
WO04063185; WO04063186; WO0130774(A1); WO0100610; WO0168648;
WO04022553; WO04022057; US2004116494; WO03039545; WO2004022553;
US2005049265; WO0224679(A1); US6562811; WO0244153(A1); WO03076447
(A1); WO03076447; US6869956; WO05011609; WO02094813; WO0246170;
WO0246171; WO0230353; WO0230423(A1); WO030866309(A2); WO0241843
(A2); WO03040131(A1); WO03048152(A2).
4. (a) Murata, T.; Shimada, M.; Sakakibara, S.; Yoshino, T.; Kadono, H.; Masuda, T.;
Shimazaki, M.; Shintani, T.; Fuchikami, K.; Sakai, K.; Inbe, H.; Takeshita, K.; Niki,
T.; Umeda, M.; Bacon, K. B.; Ziegelbauer, K. B.; Lowingera, T. B. Bioorg. Med.
Chem. Lett. 2003, 13, 913; (b) Murata, T.; Shimada, M.; Kadono, H.; Sakakibara,
S.; Yoshino, T.; Masuda, T.; Shimazaki, M.; Shintani, T.; Fuchikami, K.; Bacon, K.
B.; Ziegelbauer, K. B.; Lowinger, T. B. Bioorg. Med. Chem. Lett. 2004, 14, 4013; (c)
Murata, T.; Shimada, M.; Sakakibara, S.; Yoshino, T.; Masuda, T.; Shintani, T.;
Sato, H.; Koriyama, Y.; Fukushima, K.; Nunami, N.; Yamauchi, M.; Fuchikami,
K.; Komura, H.; Watanabe, A.; Ziegelbauer, K. B.; Bacon, K. B.; Lowinger, T. B.
Bioorg. Med. Chem. Lett. 2004, 14, 4019; (d) Burke, J. R.; Pattol, M. A.; Gregor, K.
R.; Brassil, P. J.; MacMaster, J. F.; McIntyre, K. W.; Yang, X.; Iotzova, V. S.; Clarke,
12. (a) The protocols for IKKb inhibition and the HeLa NF-
are described in reference 5.; The procedure for human whole blood LPS–TNF
assay has been described, see (b) Regan, J. et al J. Med. Chem. 2003, 46, 4676;
The mouse LPS/TNF- assay was performed according to procedure
jB reporter gene assay
a
a
a
previously described, except that mice were pre-dosed with test compounds
60 min prior to LPS challenge, see (c) Regan, J. et al J. Med. Chem. 2002, 45, 2994.
13. The possibility that the compound decomposed in plasma was ruled out by a
plasma stability study.
14. IKK
development of lymphoid organs and inflammatory resolution. It is generally
considered desirable to avoid inhibiting IKK in developing IKKb inhibitors.
a is one of the catalytic subunits in the IKK complex with roles in
a
See: (a) Hayden, M. S.; Ghosh, S. Genes Dev. 2004, 18, 2195; (b) Lawrence, T.;
Bebien, M.; Liu, G. Y.; Nizet, V.; Karin, M. Nature 2005, 434, 1138.
15. (a) Serine/threonine kinase panel: MKK1, MAPK2/ERK2, JNK/SAPK1c, SAPK2a/
p38, SAPK2b/p38b2, SAPK3/p38g, SAPK4/p38d, MAPKAP-K1a, MAPKAP-K2,
MSK1, PRAK, PKA, PKCa, PDK1, PKBDPH, SGK, S6K1, GSK3b, ROCK-II, AMPK,
CHK1, CK2, PHOS.KINASE, Lck, CSK, CDK2/cyclin A, CK1, DYRK1a, PP2a.; (b)
Tyrosine kinase panel: Btk, Eck, EGFR, FGFR3, Hek, HGFR, IGF1R, IR, Itk, Lyn,
PDGFRa, Syk, TrkA, VEGFR1.