Structure-based discovery of C-2 substituted imidazo-pyrrolopyridine JAK1 inhibitors with improved selectivity over JAK2

Bioorganic and Medicinal Chemistry Letters

Volumn 22, Issue 24, 2012, Pages 7627-7633

  Labadie, Sharada ^a   Dragovich, Peter S ^a   Barrett, Kathy ^a   Blair, Wade S ^a   Bergeron, Philippe ^a   Chang, Christine ^a   Deshmukh, Gauri ^a   Eigenbrot, Charles ^a   Ghilardi, Nico ^a   Gibbons, Paul ^a   Hurley, Christopher A ^b   Johnson, Adam ^a   Kenny, Jane R ^a   Kohli, Pawan Bir ^a   Kulagowski, Janusz J ^b   Liimatta, Marya ^a   Lupardus, Patrick J ^a   Mendonca, Rohan ^b   Murray, Jeremy M ^a   Pulk, Rebecca ^a   Shia, Steven ^a   Steffek, Micah ^a   Ubhayakar, Savita ^a   Ultsch, Mark ^a   Van Abbema, Anne ^a   Ward, Stuart ^b   Zak, Mark ^a   more..

^a GENENTECH INC   (United States)

^b Argenta Discovery Ltd   (United Kingdom)

Author keywords

Imidazo pyrrolopyridines; JAK1 selective inhibitors; Rheumatoid arthritis; Structure based design

Indexed keywords

AMINO ACID; JANUS KINASE 1; JANUS KINASE 2; PYRIDINE DERIVATIVE;

ARTICLE; CELL POLARITY; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG POTENCY; DRUG SELECTIVITY; ENZYME INHIBITION; LIVER CELL; LIVER MICROSOME; SUBSTITUTION REACTION; X RAY;

ANIMALS; CRYSTALLOGRAPHY, X-RAY; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DISCOVERY; HUMANS; IMIDAZOLES; JANUS KINASE 1; JANUS KINASE 2; MALE; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PROTEIN KINASE INHIBITORS; PYRIDINES; PYRROLES; RATS; RATS, SPRAGUE-DAWLEY; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84870239048     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2012.10.008     Document Type: Article

References (24)

1. I.B. McInnes, and G. Schett Nat. Rev. Immunol. 7 2007 429
2. R.F. Van Vollenhoven Nat. Rev. Rheumatol. 5 2009 531
3. P.C. Heinrich, I. Behrmann, G. Müller-Newen, F. Schaper, and L. Graeve J. Biochem. 334 1998 297
4. L. Song, and C. Schindler JAK-STAT Signalling R.A. Bradshaw, E.A. Dennis, The Handbook of Cell Signalling Vol. 3 2010 Elsevier Inc. San Diego 2041 2nd ed.
5. K. Shuai, and B. Liu Nat. Rev. Immunol. 3 2003 900
6. K. Ghoreschi, A. Laurence, and J. O'Shea J. Immunol. Rev. 228 2009 273
7. J.E. Darnell Jr. Science 277 1997 1630
8. J.S. Smolen, A. Beaulieu, A. Rubbert-Roth, C. Ramos-Remus, J. Rovensky, E. Alecock, T. Woodworth, and R. Alten Lancet 371 2008 987
9. R. Fleischmann, M. Cutolo, M.C. Genovese, E.B. Lee, K.S. Kanik, S. Sadis, C.A. Connell, D. Gruben, S. Krishnaswami, G. Wallenstein, B.E. Wilkinson, and S.H. Zwillich Arthritis Rheum. 64 2012 617
10. Q. Lin, D. Meloni, Y. Pan, M. Xia, J. Rodgers, S. Shepard, M. Li, L. Galya, B. Metcalf, T.Y. Yue, P. Liu, and J. Zhou Org. Lett. 1 2009 1999
11. A related small molecule JAK1/2 inhibitor (INCB028050/LY3009104) is being evaluated for rheumatoid arthritis:Greenwald, M. W.; Fidelus-Gort, R.; Levy, R.; Liang, J.; Vaddi, K.; Williams, W. V.; Newton, R. Arthritis Rheum, doi: http://dx.doi.org/10.1002/art.29936.
12. J.S. Fridman, P.A. Scherle, R. Collins, T.C. Burn, Y. Li, J. Li, M.B. Covington, B. Thomas, P. Collier, M.F. Favata, X. Wen, J. Shi, R. McGee, P.J. Haley, S. Shepard, J.D. Rodgers, G.H. Yaleswaram, R.C. Newton, B. Metcalf, S.M. Friedman, and K. Vaddi J. Immunol. 184 2010 5298
13. E. Parganas, D. Wang, D. Stravopodis, D.J. Topham, J.C. Marine, S. Teglund, E.F. Vanin, S. Bodner, O.R. Colamonici, J.M. van Deursen, G. Grosveld, and J.N. Ihle Cell 93 1998 385
14. C. Haan, C. Rolvering, F. Raulf, M. Kapp, P. Druckes, G. Thoma, I. Behrmann, and H.G. Zerwes Chem. Biol. 18 2011 314
15. B.A. Witthuhn, F.W. Quelle, O. Silvennoinen, T. Yi, B. Tang, O. Miura, and J.N. Ihle Cell 74 1993 227
16. Kontzias, A.; Laurence, A.; Gadina, M.; O'Shea, J. J. F1000 Medicine Reports, 2012, doi: http://dx.doi.org/10:3410/M4-5.
17. M. Zak, R. Mendonca, M. Balazs, K. Barrett, B. Bergeron, W. Blair, C. Chang, G. Deshmukh, J. DeVoss, P.S. Dragovich, C. Eigenbrot, N. Ghilardi, P. Gibbons, S. Gradl, H. Hamman, E.J. Hanan, E. Harstad, P.R. Hewitt, C.A. Hurley, T. Jin, A. Johnson, T. Johnson, J.R. Kenny, M.F.T. Koehler, P.B. Kohli, J.J. Kulagowski, S. Labadie, J. Liao, M. Liimatta, Z. Lin, P.J. Lupardus, R.J. Maxey, J. Murray, R. Pulk, M. Rodriguez, S. Savage, S. Shia, M. Steffek, S. Ubhayakar, M. Ultsch, A. Van Abbema, S.I. Ward, L. Xiao, and Y. Xiao J. Med. Chem. 55 2012 6176
18. J.J. Kulagowski, W. Blair, R.J. Bull, C. Chang, G. Deshmukh, H.J. Dyke, C. Eigenbrot, N. Ghilardi, P. Gibbons, T.K. Harrison, P.R. Hewitt, M. Liimatta, C.A. Hurley, A. Johnson, T. Johnson, J. Kenny, P.B. Kohli, R.J. Maxey, R. Mendonca, K. Mortara, J. Murray, R. Narukulla, S. Shia, M. Steffek, S. Ubhayakar, M. Ultsch, A. Van Abbema, S.I. Ward, B. Waszkowycz, and M. Zak J. Med. Chem. 55 2012 5901
19. Broo, A.; Holm, P.; Judkins, R.; Li, L.; Lindstedt-Alstermark, E.-L.; Snadberg, P.; Swanson, M.; Weidole, L.; Mirickmann, K.; Patent Application WO 2006/073366, 2006.
20. In some instances, when the imidate formation with triethyloxonium tetrafluoroborate was performed in THF, polymerization of the solvent occurred to form a viscous mass and the reaction could not be continued. Similar observations were previously reported: A.P. Vartak, and P.A. Crooks Org. Process Res. Dev. 13 2009 415
21. Imidate formation can also be carried out in DCM: A.J. Kiessling, and C.K. McClure Synth. Commun. 27 1997 923
22. For chiral separation of cis-/trans-enantiomers of 3-aminocyclohexanol, see: C.E. Brocklehurst, K. Laumen, L. La Vecchia, D. Shaw, and M. Vögtle Org. Process Res. Dev. 15 2011 294
23. S. Caille, J. Boni, G.B. Cox, M.F. Faul, P. Franco, S. Khattabi, L.M. Klingensmith, J.F. Larrow, J.K. Lee, M.J. Martinelli, L.M. Miller, G.A. Moniz, K. Sakai, J.S. Tedrow, and B.K. Hansen Org. Process Res. Dev. 1 2010 133
24. P. Ertl, B. Rohde, and P. Selzer J. Med. Chem. 43 2000 3714