Design and optimization of selective protein kinase C θ (PKCθ) inhibitors for the treatment of autoimmune diseases

Journal of Medicinal Chemistry

Volumn 56, Issue 5, 2013, Pages 1799-1810

  Jimenez, Juan Miguel ^a   Boyall, Dean ^a   Brenchley, Guy ^a   Collier, Philip N ^a   Davis, Christopher J ^a   Fraysse, Damien ^a   Keily, Shazia B ^a   Henderson, Jaclyn ^a   Miller, Andrew ^a   Pierard, Francoise ^a   Settimo, Luca ^a   Twin, Heather C ^a   Bolton, Claire M ^a   Curnock, Adam P ^a   Chiu, Peter ^a   Tanner, Adam J ^a   Young, Stephen ^a  

^a VERTEX PHARMACEUTICALS   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 [4 (3 CHLORO 5 FLUORO 6 (1H PYRAZOLO[3,4 BETA]PYRIDIN 3 YL)PYRIDIN 2 YL)PIPERAZIN-2-YL] 3 METHYLBUTAN 2 OL; 2 [4 (3,5 DIFLUORO 6 (1H PYRAZOLO[3,4 BETA]PYRIDIN 3 YL) PYRIDIN 2 YL)PIPERAZIN 2 YL] 3 METHYLBUTAN 2 OL; 3 [3 FLUORO 6 (3 ISOBUTYLPIPERAZIN 1 YL)PYRIDIN 2 YL] 1H PYRAZOLO[3,4 BETA]PYRIDINE; CYCLOSPORIN A; PIPERAZINE DERIVATIVE; PROTEIN KINASE C INHIBITOR; PROTEIN KINASE C THETA; PYRIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; AUTOIMMUNE DISEASE; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG DESIGN; DRUG POTENCY; DRUG SELECTIVITY; HUMAN; IMMUNE RESPONSE; IMMUNITY; LIPOPHILICITY; NONHUMAN; PROCESS OPTIMIZATION; RAT; T LYMPHOCYTE;

ANIMALS; AUTOIMMUNE DISEASES; DRUG DESIGN; HUMANS; INHIBITORY CONCENTRATION 50; INTERLEUKIN-2; ISOENZYMES; LYMPHOCYTE ACTIVATION; MICE; PIPERAZINES; PROTEIN KINASE C; PROTEIN KINASE INHIBITORS; PYRIDINES; T-LYMPHOCYTES;

EID: 84875145829     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm301465a     Document Type: Article

References (46)

1. Rosse, C.; Linch, M.; Kermorgant, S.; Cameron, A. J.; Boeckeler, K.; Parker, P. J. PKC and the control of localized signal dynamics Nat. Rev. Mol. Cell Biol. 2010, 11, 103-112
2. Baier, G.; Telford, D.; Giampa, L.; Coggeshall, K. M.; Baier-Bitterlich, G.; Isakov, N.; Altman, A. Molecular cloning and characterization of PKC theta, a novel member of the protein kinase C (PKC) gene family expressed predominantly in hematopoietic cells J. Biol. Chem. 1993, 268, 4997-5004 (Pubitemid 23081623)
3. Sun, Z.; Arendt, C. W.; Ellmeier, W.; Schaeffer, E. M.; Sunshine, M. J.; Gandhi, L.; Annes, J.; Petrzilka, D.; Kupfer, A.; Schwartzberg, P. L.; Littman, D. R. PKC-theta is required for TCR-induced NF-kappaB activation in mature but not immature T lymphocytes Nature 2000, 404, 402-407 (Pubitemid 30164343)
4. Pfeifhofer, C.; Kofler, K.; Gruber, T.; Tabrizi, N. G.; Lutz, C.; Maly, K.; Leitges, M.; Baier, G. Protein kinase C theta affects Ca2+ mobilization and NFAT cell activation in primary mouse T cells J. Exp. Med. 2003, 197, 1525-1535 (Pubitemid 36682549)
5. Manicassamy, S.; Sadim, M.; Ye, R. D.; Sun, Z. Differential roles of PKC-theta in the regulation of intracellular calcium concentration in primary T cells J. Mol. Biol. 2006, 355, 347-359 (Pubitemid 41785743)
6. Baier-Bitterlich, G.; Uberall, F.; Bauer, B.; Fresser, F.; Wachter, H.; Grunicke, H.; Utermann, G.; Altman, A.; Baier, G. Protein kinase C-theta isoenzyme selective stimulation of the transcription factor complex AP-1 in T lymphocytes Mol. Cell. Biol. 1996, 16, 1842-50
7. Coudronniere, N.; Villalba, M.; Englund, N.; Altman, A. NF-kappa B activation induced by T cell receptor/CD28 costimulation is mediated by protein kinase C-theta Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 3394-3399 (Pubitemid 30183313)
8. Lin, X.; O'Mahony, A.; Mu, Y.; Geleziunas, R.; Greene, W. C. Protein kinase C-theta participates in NF-kappaB activation induced by CD3-CD28 costimulation through selective activation of IkappaB kinase beta Mol. Cell. Biol. 2000, 20, 2933-40 (Pubitemid 30183513)
9. Bertolotto, C.; Maulon, L.; Filippa, N.; Baier, G.; Auberger, P. Protein kinase C theta and epsilon promote T-cell survival by a rsk-dependent phosphorylation and inactivation of BAD J. Biol. Chem. 2000, 275, 37246-37250 (Pubitemid 32002146)
10. Villalba, M.; Bushway, P.; Altman, A. Protein kinase C-theta mediates a selective T cell survival signal via phosphorylation of BAD J. Immunol. 2001, 166, 5955-5963 (Pubitemid 32440719)
11. Barouch-Bentov, R.; Lemmens, E. E.; Hu, J.; Janssen, E. M.; Droin, N. M.; Song, J.; Schoenberger, S. P.; Altman, A. Protein kinase C-theta is an early survival factor required for differentiation of effector CD8+ T cells J. Immunol. 2005, 175, 5126-5134 (Pubitemid 41456396)
12. Manicassamy, S.; Gupta, S.; Huang, Z.; Sun, Z. Protein kinase C-theta-mediated signals enhance CD4+ T cell survival by up-regulating Bcl-xL J. Immunol. 2006, 176, 6709-6716 (Pubitemid 43787854)
13. Berg-Brown, N. N.; Gronski, M. A.; Jones, R. G.; Elford, A. R.; Deenick, E. K.; Odermatt, B.; Littman, D. R.; Ohashi, P. S. PKCtheta signals activation versus tolerance in vivo J. Exp. Med. 2004, 199, 743-752 (Pubitemid 38375194)
14. Marsland, B. J.; Soos, T. J.; Spath, G.; Littman, D. R.; Kopf, M. Protein kinase C theta is critical for the development of in vivo T helper (Th)2 cell but not Th1 cell responses J. Exp. Med. 2004, 200, 181-189 (Pubitemid 38982177)
15. Giannoni, F.; Lyon, A. B.; Wareing, M. D.; Dias, P. B.; Sarawar, S. R. Protein kinase C theta is not essential for T-cell-mediated clearance of murine gammaherpesvirus 68 J. Virol. 2005, 79, 6808-6813 (Pubitemid 40677313)
16. Marsland, B. J.; Nembrini, C.; Schmitz, N.; Abel, B.; Krautwald, S.; Bachmann, M. F.; Kopf, M. Innate signals compensate for the absence of PKC-{theta} during in vivo CD8(+) T cell effector and memory responses Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 14374-14379 (Pubitemid 41429705)
17. Marsland, B. J.; Nembrini, C.; Grun, K.; Reissmann, R.; Kurrer, M.; Leipner, C.; Kopf, M. TLR ligands act directly upon T cells to restore proliferation in the absence of protein kinase C-theta signaling and promote autoimmune myocarditis J. Immunol. 2007, 178, 3466-3473 (Pubitemid 46417611)
18. Salek-Ardakani, S.; So, T.; Halteman, B. S.; Altman, A.; Croft, M. Differential regulation of Th2 and Th1 lung inflammatory responses by protein kinase C theta J. Immunol. 2004, 173, 6440-6447 (Pubitemid 39487805)
19. Salek-Ardakani, S.; So, T.; Halteman, B. S.; Altman, A.; Croft, M. Protein kinase Ctheta controls Th1 cells in experimental autoimmune encephalomyelitis J. Immunol. 2005, 175, 7635-7641 (Pubitemid 41713463)
20. Tan, S. L.; Zhao, J.; Bi, C.; Chen, X. C.; Hepburn, D. L.; Wang, J.; Sedgwick, J. D.; Chintalacharuvu, S. R.; Na, S. Resistance to experimental autoimmune encephalomyelitis and impaired IL-17 production in protein kinase C theta-deficient mice J. Immunol. 2006, 176, 2872-2879
21. Anderson, K.; Fitzgerald, M.; Dupont, M.; Wang, T.; Paz, N.; Dorsch, M.; Healy, A.; Xu, Y.; Ocain, T.; Schopf, L.; Jaffee, B.; Picarella, D. Mice deficient in PKC theta demonstrate impaired in vivo T cell activation and protection from T cell-mediated inflammatory diseases Autoimmunity 2006, 39, 469-478 (Pubitemid 44575079)
22. Healy, A. M.; Izmailova, E.; Fitzgerald, M.; Walker, R.; Hattersley, M.; Silva, M.; Siebert, E.; Terkelsen, J.; Picarella, D.; Pickard, M. D.; LeClair, B.; Chandra, S.; Jaffee, B. PKC-theta-deficient mice are protected from Th1-dependent antigen-induced arthritis J. Immunol. 2006, 177, 1886-1893 (Pubitemid 44092528)
23. Nagahama, K.; Ogawa, A.; Shirane, K.; Shimomura, Y.; Sugimoto, K.; Mizoguchi, A. Protein kinase C theta plays a fundamental role in different types of chronic colitis Gastroenterology 2008, 134, 459-469 (Pubitemid 351173043)
24. Skvara, H.; Dawid, M.; Kleyn, E.; Wolff, B.; Meingassner, J. G.; Knight, H.; Dumortier, T.; Kopp, T.; Fallahi, N.; Stary, G.; Burkhart, C.; Grenet, O.; Wagner, J.; Hijazi, Y.; Morris, R. E.; McGeown, C.; Rordorf, C.; Griffiths, C. E.; Stingl, G.; Jung, T. The PKC inhibitor AEB071 may be a therapeutic option for psoriasis J. Clin. Invest. 2008, 118, 3151-3159
25. Budde, K.; Sommerer, C.; Becker, T.; Asderakis, A.; Pietruck, F.; Grinyo, J. M.; Rigotti, P.; Dantal, J.; Ng, J.; Barten, M. J.; Weber, M. Sotrastaurin, a novel small molecule inhibiting protein kinase C: first clinical results in renal-transplant recipients Am. J. Transplant. 2010, 10, 571-581
26. Wagner, J.; von Matt, P.; Sedrani, R.; Albert, R.; Cooke, N.; Ehrhardt, C.; Geiser, M.; Rummel, G.; Stark, W.; Strauss, A.; Cowan-Jacob, S. W.; Beerli, C.; Weckbecker, G.; Evenou, J. P.; Zenke, G.; Cottens, S. Discovery of 3-(1 H -indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione (AEB071), a potent and selective inhibitor of protein kinase C isotypes J. Med. Chem. 2009, 52, 6193-6196
27. Wagner, J.; von Matt, P.; Faller, B.; Cooke, N. G.; Albert, R.; Sedrani, R.; Wiegand, H.; Jean, C.; Beerli, C.; Weckbecker, G.; Evenou, J. P.; Zenke, G.; Cottens, S. Structure-activity relationship and pharmacokinetic studies of sotrastaurin (AEB071), a promising novel medicine for prevention of graft rejection and treatment of psoriasis J. Med. Chem. 2011, 54, 6028-6039
28. Subrath, J.; Wang, D.; Wu, B.; Niu, C.; Boschelli, D. H.; Lee, J.; Yang, X.; Brennan, A.; Chaudhary, D. C-5 Substituted heteroaryl 3- pyridinecarbonitriles as PKCtheta inhibitors: part I Bioorg. Med. Chem. Lett. 2009, 19, 5423-5425
29. Prashad, A. S.; Wang, D.; Subrath, J.; Wu, B.; Lin, M.; Zhang, M. Y.; Kagan, N.; Lee, J.; Yang, X.; Brennan, A.; Chaudhary, D.; Xu, X.; Leung, L.; Wang, J.; Boschelli, D. H. C-5 substituted heteroaryl-3-pyridinecarbonitriles as PKCtheta inhibitors: part II Bioorg. Med. Chem. Lett. 2009, 19, 5799-5802
30. Cole, D. C.; Asselin, M.; Brennan, A.; Czerwinski, R.; Ellingboe, J. W.; Fitz, L.; Greco, R.; Huang, X.; Joseph-McCarthy, D.; Kelly, M. F.; Kirisits, M.; Lee, J.; Li, Y.; Morgan, P.; Stock, J. R.; Tsao, D. H.; Wissner, A.; Yang, X.; Chaudhary, D. Identification, characterization and initial hit-to-lead optimization of a series of 4-arylamino-3-pyridinecarbonitrile as protein kinase C theta (PKCtheta) inhibitors J. Med. Chem. 2008, 51, 5958-5963
31. Dushin, R. G.; Nittoli, T.; Ingalls, C.; Boschelli, D. H.; Cole, D. C.; Wissner, A.; Lee, J.; Yang, X.; Morgan, P.; Brennan, A.; Chaudhary, D. Synthesis and PKCtheta inhibitory activity of a series of 4-indolylamino-5-phenyl-3- pyridinecarbonitriles Bioorg. Med. Chem. Lett. 2009, 19, 2461-2463
32. Wu, B.; Boschelli, D. H.; Lee, J.; Yang, X.; Chaudhary, D. Second generation 4-(4-methyl-1 H -indol-5-ylamino)-2-phenylthieno[2,3- b ]pyridine-5-carbonitrile PKCtheta inhibitors Bioorg. Med. Chem. Lett. 2009, 19, 766-769
33. Boschelli, D. H.; Wu, B.; Barrios Sosa, A. C.; Chen, J.; Asselin, M.; Cole, D. C.; Lee, J.; Yang, X.; Chaudhary, D. Synthesis and PKCtheta inhibitory activity of a series of 4-(indol-5-ylamino)thieno[2,3- b ]pyridine-5- carbonitriles Bioorg. Med. Chem. Let. 2008, 18, 2850-2853 (Pubitemid 351622044)
34. Nathan Tumey, L.; Boschelli, D. H.; Lee, J.; Chaudhary, D. 2-Alkenylthieno[2,3- b ]pyridine-5-carbonitriles: potent and selective inhibitors of PKCtheta Bioorg. Med. Chem. Lett. 2008, 18, 4420-4423
35. Boschelli, D. H.; Wang, D.; Prashad, A. S.; Subrath, J.; Wu, B.; Niu, C.; Lee, J.; Yang, X.; Brennan, A.; Chaudhary, D. Optimization of 5-phenyl-3-pyridinecarbonitriles as PKCtheta inhibitors Bioorg. Med. Chem. Lett. 2009, 19, 3623-3626
36. Boschelli, D. H.; Subrath, J.; Niu, C.; Wu, B.; Wang, Y.; Lee, J.; Brennan, A.; Ho, M.; Deng, B.; Yang, X.; Xu, X.; Leung, L.; Wang, J.; Atherton, J.; Chaudhary, D. Optimization of 5-vinylaryl-3-pyridinecarbonitriles as PKCtheta inhibitors Bioorg. Med. Chem. Lett. 2010, 20, 1965-1968
37. Niu, C.; Boschelli, D. H.; Tumey, L. N.; Bhagirath, N.; Subrath, J.; Shim, J.; Wang, Y.; Wu, B.; Eid, C.; Lee, J.; Yang, X.; Brennan, A.; Chaudhary, D. First generation 5-vinyl-3-pyridinecarbonitrile PKCtheta inhibitors Bioorg. Med. Chem. Lett. 2009, 19, 5829-5832
38. Shim, J.; Eid, C.; Lee, J.; Liu, E.; Chaudhary, D.; Boschelli, D. H. Synthesis and PKCtheta inhibitory activity of a series of 5-vinyl phenyl sulfonamide-3-pyridinecarbonitriles Bioorg. Med. Chem. Lett. 2009, 19, 6575-6577
39. Cywin, C. L.; Dahmann, G.; Prokopowicz, A. S., 3rd; Young, E. R.; Magolda, R. L.; Cardozo, M. G.; Cogan, D. A.; Disalvo, D.; Ginn, J. D.; Kashem, M. A.; Wolak, J. P.; Homon, C. A.; Farrell, T. M.; Grbic, H.; Hu, H.; Kaplita, P. V.; Liu, L. H.; Spero, D. M.; Jeanfavre, D. D.; O'Shea, K. M.; White, D. M.; Woska, J. R., Jr.; Brown, M. L. Discovery of potent and selective PKC-theta inhibitors Bioorg. Med. Chem. Lett. 2007, 17, 225-230 (Pubitemid 44959959)
40. Boschelli, D. H. Small molecule inhibitors of PKCTheta as potential antiinflammatory therapeutics Curr. Top. Med. Chem. 2009, 9, 640-654
41. Jimenez, J.-M.; Davis, J. C.; Boyall, D.; Fraysee, D.; Knegtel, R.; Settimo, L.; Young, S.; Bolton, C.; Chiu, P.; Curnock, A.; Rasmussen, R.; Tanner, A.; Ager, I. Structure-based optimization of aminopyridines as PKCθ inhibitors Bioorg. Med. Chem. Lett. 2012, 22, 4645-4649
42. Leeson, P. D.; Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry Nat. Rev. Drug Discovery 2007, 6, 881-890 (Pubitemid 350042396)
43. Mecklenbrauker, I.; Saijo, K.; Zheng, N. Y.; Leitges, M.; Tarakhovsky, A. Protein kinase Cdelta controls self-antigen-induced B-cell tolerance Nature 2002, 416, 860-865 (Pubitemid 34453743)
44. Miyamoto, A.; Nakayama, K.; Imaki, H.; Hirose, S.; Jiang, Y.; Abe, M.; Tsukiyama, T.; Nagahama, H.; Ohno, S.; Hatakeyama, S.; Nakayama, K. I. Increased proliferation of B cells and auto-immunity in mice lacking protein kinase C delta Nature 2002, 416, 865-869 (Pubitemid 34453744)
45. Gill, A. L.; Verdonk, M.; Boyle, R. G.; Taylor, R. A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development Curr. Top. Med. Chem. 2007, 7, 1408-1422 (Pubitemid 47471238)
46. Rummel, G.; Stark, W.; Strauss, A.; Wagner, J. Three Dimensional Structure of the Catalytic Domain of Protein C theta, Methods and Use Thereof. PCT Int. Appl. WO2004076654, 2004.