70
X. Huang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 65–70
8. Ulfgren, A. K.; Andersson, U.; Engstrom, M.; Klareskog, L.; Maini, R. N.; Taylor, P.
C. Arthritis Rheum. 2000, 43, 2391.
have quickly identified key conformational preference for branch 2
as para-piperazine substituted phenyl and branch 3 as ortho-
substituted biphenyl. Localized SAR studies (third degree SAR) on
branch 3 have helped to improve the binding activity to single digit
nanomolar and cellular activity less than 500 nM and identify 2-(4-
methoxypyridin-3-yl)benzyl (in 28) and 2-(pyrimidin-5-yl)benzyl
(in 26) as two of the preferred functional groups responsible for
improved binding and cellular activity. The importance of these
groups is further confirmed by other series of MK2 inhibitors with
the same core structure which will be reported in due courses.23
9. Schett, G.; Zwerina, J.; Firestein, G. Ann. Rheum. Dis. 2008, 67, 909.
10. Alten, R. E.; Zerbini, C.; Jeka, S.; Irazoque, F.; Khatib, F.; Emery, P.; Bertasso, A.;
Rabbia, M.; Caulfield, J. P. Ann. Rheum. Dis. 2010, 69, 364.
11. Kumar, S.; Boehm, J.; Lee, J. C. Nat. Rev. Drug Disc. 2003, 2, 717.
12. Schindler, J. F.; Monahan, J. B.; Smith, W. G. J. Dent. Res. 2007, 86, 800.
13. Kotlyarov, A.; Neininger, A.; Schubert, C.; Eckert, R.; Birchmeier, C.; Volk, H.-D.;
Gaestel, M. Nat. Cell Biol. 1999, 1, 94.
14. Shi, Y.; Kotlyarov, A.; Laab, K.; Gruber, A. D.; Butt, E.; Marcus, K.; Meyer, H. E.;
Friedrich, A.; Volk, H.-D.; Gaestel, M. Mol. Cell. Biol. 2003, 23, 7732.
15. Ronkina, N.; Kotlyarov, A.; Dittrich-Breiholz, O.; Kracht, M.; Hitti, E.; Milarski,
K.; Askew, R.; Marusic, S.; Lin, L.-L.; Gaestel, M.; Telliez, J.-B. Mol. Cell. Biol. 2007,
27, 170.
16. Hegen, M.; Gaestel, M.; Nickerson-Nutter, C. L.; Lin, L.-L.; Telliez, J.-B. J.
Immunol. 2006, 177, 1913.
Acknowledgments
17. Gorska, M. M.; Liang, Q.; Stafford, S. J.; Goplen, N.; Dharajiya, N.; Guo, L.; Sur, S.;
Gaestel, M.; Alam, R. J. Exp. Med. 2007, 204, 1637.
18. Lopes, L. B.; Flynn, C.; Komalavilas, P.; Panitch, A.; Brophy, C. M.; Seald, B. L.
Biochem. Biophys. Res. Commun. 2009, 382, 535.
19. Anderson, D. R.; Meyers, M. J.; Kurumbail, R. G.; Caspers, N.; Poda, G. I.; Long, S.
A.; Pierce, B. S.; Mahoney, M. W.; Mourey, R. J.; Parikh, M. D. Bioorg. Med. Chem.
Lett. 2009, 19, 4882.
20. Anderson, D. R.; Meyers, M. J.; Kurumbail, R. G.; Caspers, N.; Poda, G. I.; Long, S.
A.; Pierce, B. S.; Mahoney, M. W.; Mourey, R. J. Bioorg. Med. Chem. Lett. 2009, 19,
4878.
21. Velcicky, J.; Feifel, R.; Hawtin, S.; Heng, R.; Huppertz, C.; Koch, G.; Kroemer, M.;
Moebitz, H.; Revesz, L.; Scheufler, C.; Schlapbach, A. Bioorg. Med. Chem. Lett.
2010, 20, 1293–1297.
22. Huang, X.; Shipps, G. W.; Cheng, C. C.; Spacciapoli, P.; Zhang, X.; McCoy, M. A.;
Wyss, D. F.; Yang, X.; Achab, A.; Soucy, K.; Montavon, D. K.; Murphy, D. M.;
Whitehurst, C. E. ACS Med. Chem. Lett. 2011, 2, 632. and references cited there
in.
23. (a) Qin, J.; Dhondi, P.; Huang, X.; Aslanian, R. G.; Fossetta, J. D.; Palani, A. ACS
Med. Chem. Lett., accepted for publication.; (b) Xiao, D.; Palani, A.; Aslanian, R.
G.; Degrado, S.; Huang, X.; Zhou, W.; Sofolarides, M.; Chen, X. Patent WO
2011075375 A1, 2011.
We thank Drs. Christopher Boyce and Songnian Lin for comments
on the preparation of the manuscript. We thank Drs. John Piwinski,
William Greenlee, and Catherine Strader for their strong support.
We thank Drs. Alexei Buevich and Li-Kang Zhang for technical
support.
References and notes
1. (a) Frantz, S. Nat. Rev. Drug Disc. 2006, 5, 977; (b) Krishan, M. Pharma Biotech
2. Piachaud, B. S. Technovation 2002, 22, 81.
3. Melnikova, I.; Golden, J. Nat. Rev. Drug Disc. 2004, 3, 993.
4. Tobon, G. J.; Youinou, P.; Saraux, A. Autoimmun. Rev. 2010, 9, A288.
5. Arend, W. P.; Dayer, J. M. Arthritis Rheum. 1990, 33, 305.
6. Firestein, G. S.; Alvaro-Gracia, J. M.; Maki, R. J. Immunol. 1990, 144, 3347.
7. Rutgeerts, P.; D’Haens, G.; Targan, S.; Vasiliauskas, E.; Hanauer, S. B.; Present, D.
H.; Mayer, L.; Van Hogezand, R. A.; Braakman, T.; DeWoody, K. L.; Shaible, T. F.;
Van Deventer, S. J. H. Gastroenterology 1999, 117, 761.