Tetrahydroindazoles as interleukin-2 inducible T-cell kinase inhibitors. Part II. Second-generation analogues with enhanced potency, selectivity, and pharmacodynamic modulation in vivo

Journal of Medicinal Chemistry

Volumn 58, Issue 9, 2015, Pages 3806-3816

  Burch, Jason D ^a   Barrett, Kathy ^a   Chen, Yuan ^a   DeVoss, Jason ^a   Eigenbrot, Charles ^a   Goldsmith, Richard ^a   Ismaili, M Hicham A ^a   Lau, Kevin ^a   Lin, Zhonghua ^a   Ortwine, Daniel F ^a   Zarrin, Ali A ^a   McEwan, Paul A ^b   Barker, John J ^b   Ellebrandt, Claire ^c   Kordt, Daniel ^c   Stein, Daniel B ^c   Wang, Xiaolu ^c   Chen, Yong ^d   Hu, Baihua ^d   Xu, Xiaofeng ^d   Yuen, Po Wai ^d   Zhang, Yamin ^d   Pei, Zhonghua ^a   more..

^a GENENTECH INC   (United States)

^b EVOTEC UK LTD   (United Kingdom)

^c EVOTEC AG   (Germany)

^d Pharmaron Beijing Co Ltd   (China)

Author keywords

[No Author keywords available]

Indexed keywords

6,6 DIMETHYL N [1 [(1 OXIDOTETRAHYDRO 2H THIOPYRAN 4 YL) (PHENYL)METHYL] IH PYRAZOL 4 YL] 4,5,6,7 TETRAHYDRO 1H INDAZOLE 3 CARBOXAMIDE; CD3 ANTIBODY; INDAZOLE DERIVATIVE; INTERLEUKIN 13; INTERLEUKIN 2; INTERLEUKIN 2 INDUCIBLE T CELL KINASE; N (1 BENZYL 1H PYRAZOL 4 YL) 5,5 DIFLUORO 5A METHYL 1,,4,4A,5,5A,6 HEXAHYDROCYCLOPROPA[F]INDAZOLE 3 CARBOXAMIDE; N [1 [(1,1 DIOXIDOTETRAHYDRO 2H THIOPYRAN 2 YL)(PHENYL)METHYL] 1H PYRAZOL 4 YL] 5,5 DIFLUORO 5A METHYL 1,,4,4A,5,5A,6 HEXAHYDROCYCLOPROPA[F]INDAZOLE 3 CARBOXAMIDE; N [1 [(1,1 DIOXIDOTETRAHYDRO 2H THIOPYRAN 2 YL)(PHENYL)METHYL] 1H PYRAZOL 4 YL] 6,6 DIMETHYL 4,5,6,7 TETRAHYDRO 1H INDAZOLE 3 CARBOXAMIDE; N [1 [(1,1 DIOXIDOTETRAHYDRO 2H THIOPYRAN 3 YL)(PHENYL)METHYL] 1H PYRAZOL 4 YL] 6,6 DIMETHYL 4,5,6,7 TETRAHYDRO 1H INDAZOLE 3 CARBOXAMIDE; N [1 [(1,1 DIOXIDOTETRAHYDRO 2H THIOPYRAN 4 YL)(PHENYL)METHYL] 1H PYRAZOL 4 YL] 6,6 DIMETHYL 4,5,6,7 TETRAHYDRO 1H INDAZOLE 3 CARBOXAMIDE; N [1 [(1,1 DIOXIDOTETRAHYDROTHIOPEN 3 YL)(PHENYL)METHYL] 1H PYRAZOL 4 YL] 6,6 DIMETHYL 4,5,6,7 TETRAHYDRO 1H INDAZOLE 3 CARBOXAMIDE; PROTEIN TYROSINE KINASE; PROTEIN TYROSINE KINASE INHIBITOR; T LYMPHOCYTE RECEPTOR; UNCLASSIFIED DRUG; CYTOTOXIN; EMT PROTEIN-TYROSINE KINASE; LYMPHOCYTE ANTIGEN RECEPTOR; SULFONE; SULFOXIDE;

ANIMAL EXPERIMENT; ANTIPROLIFERATIVE ACTIVITY; ARTICLE; CELL VIABILITY ASSAY; CYTOKINE RELEASE; CYTOTOXICITY; DRUG POTENCY; ENZYME INHIBITION; FEMALE; JURKAT CELL LINE; LIVER CELL; MOUSE; NONHUMAN; PHARMACODYNAMICS; RECEPTOR BINDING; SCANNING ELECTRON MICROSCOPY; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION; T LYMPHOCYTE; X RAY CRYSTALLOGRAPHY; ANIMAL; ANTAGONISTS AND INHIBITORS; BIOSYNTHESIS; C57BL MOUSE; CELL PROLIFERATION; CHEMICAL STRUCTURE; CHEMISTRY; DRUG EFFECTS; HUMAN; METABOLISM; PHOSPHORYLATION; STEREOISOMERISM;

ANIMALS; CELL PROLIFERATION; CRYSTALLOGRAPHY, X-RAY; CYTOTOXINS; FEMALE; HUMANS; INDAZOLES; INTERLEUKIN-13; INTERLEUKIN-2; JURKAT CELLS; MICE, INBRED C57BL; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PHOSPHORYLATION; PROTEIN-TYROSINE KINASES; RECEPTORS, ANTIGEN, T-CELL; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONES; SULFOXIDES;

EID: 84929378631     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm501998m     Document Type: Article

References (34)

1. Berg, L. J.; Finkelstein, L. D.; Lucas, J. A.; Schwartzberg, P. L. Tec family kinases in T lymphocyte development and function Annu. Rev. Immunol. 2005, 23, 549-600
2. Felices, M.; Falk, M.; Kosaka, Y.; Berg, L. J. Tec kinases in T Cell and Mast Cell Signaling Adv. Immunol. 2007, 93, 145-184
3. Liu, K. Q.; Bunnell, S. C.; Gurniak, C. B.; Berg, L. J. T cell receptor-initiated calcium release is uncoupled from capacitative calcium entry in Itk-deficient T cells J. Exp. Med. 1998, 187, 1721-1727
4. Schaeffer, E. M.; Debnath, J.; Yap, G.; McVicar, D.; Liao, X. C.; Littman, D. R.; Sher, A.; Varmus, H. E.; Lenardo, M. J.; Schwartzberg, P. L. Requirement for Tec kinases Rlk and Itk in T cell receptor signaling and immunity Science 1999, 284, 638-641
5. Ellmeier, W.; Jung, S.; Sunshine, M. J.; Hatam, F.; Xu, Y.; Baltimore, D.; Mano, H.; Littman, D. R. Severe B cell deficiency in mice lacking the Tec kinase family members Tec and Btk J. Exp. Med. 2000, 192, 1611-1624
6. Liao, X. C.; Littman, D. R. Altered T cell receptor signaling and disrupted T cell development in mice lacking Itk Immunity 1995, 3, 757-769
7. Fowell, D. J.; Shinkai, K.; Liao, X. C.; Beebe, A. M.; Coffman, R. L.; Littman, D. R.; Locksley, R. M. Impaired NFATc translocation and failure of Th2 development in Itk-deficient CD4+ T cells Immunity 1999, 11, 399-409
8. Schaeffer, E. M.; Yap, G. S.; Lewis, C. M.; Czar, M. J.; McVicar, D. W.; Cheever, A. W.; Sher, A.; Schwartzberg, P. L. Mutation of Tec family kinases alters T helper cell differentiation Nature Immunol. 2001, 2, 1183-1188
9. Mueller, C.; August, A. Attenuation of immunological symptoms of allergic asthma in mice lacking the tyrosine kinase ITK J. Immunol. 2003, 170, 5056-5063
10. Sahu, N.; Mueller, C.; Fisher, A.; August, A. Differential Sensitivity to ITK Kinase Signals for T Helper 2 Cytokine Production and Chemokine-Mediated Migration J. Immunol. 2008, 180, 3833-3838
11. Das, J.; Liu, C.; Moquin, R. V.; Lin, J.; Furch, J. A.; Spergel, S. H.; McIntyre, K. W.; Shuster, D. J.; O'Day, K. D.; Penhallow, B.; Huang, C.-Y.; Kanner, S. B.; Lin, T.-A.; Dodd, J. H.; Barrish, J. C.; Wityak, J. Discovery and SAR of 2-amino-5-[(thiomethyl)aryl]thiazoles as potent and selective Itk inhibitors Bioorg. Med. Chem. Lett. 2006, 16, 2411-2415
12. Lin, T. A.; McIntyre, K.; Das, J.; Liu, C.; O'Day, K. D.; Penhallow, C.-Y.; Whitney, G. S.; Shuster, D. J.; Xia, X.; Towsend, R.; Postelnek, J.; Spergel, S. H.; Lin, J.; Moquin, R. V.; Furch, J. A.; Kamath, A. V.; Zhang, H.; Marathe, P. H.; Perez-Villar, J. J.; Doweyko, A.; Killar, L.; Dodd, J. H.; Barrish, J. C.; Wityak, J.; Kanner, S. B. Selective Itk inhibitors block T-cell activation and murine lung inflammation Biochemistry 2004, 43, 11056-11062
13. Snow, R. J.; Abeywardane, A.; Campbell, S.; Lord, J.; Kashem, M. A.; Khine, H. H.; King, J.; Kowalski, J. A.; Pullen, S. S.; Roma, T.; Roth, G. P.; Sarko, C. R.; Wilson, N. S.; Winter, M. P.; Wolak, J. P.; Cywin, C. L. Hit-to-lead studies on benzimidazole inhibitors of ITK: Discovery of a novel class of kinase inhibitors Bioorg. Med. Chem. Lett. 2007, 17, 3660-3665
14. Moriarty, K. J.; Winters, M.; Qiao, L.; Ryan, D.; DesJarlis, R.; Robinson, D.; Cook, B. N.; Kashen, M. A.; Kaplita, P. V.; Liu, L. H.; Farrell, T. M.; Khine, H. H.; King, J.; Pullen, S. S.; Roth, G. P.; Magolda, R.; Takahashi, H. Itk kinase inhibitors: initial efforts to improve the metabolic stability and the cell activity of the benzimidazole lead Bioorg. Med. Chem. Lett. 2008, 18, 5537-5540
15. Winters, M. P.; Robinson, D. J.; Khine, H. H.; Pullen, S. S.; Woska, J. R., Jr.; Raymond, E. L.; Sellati, R.; Cywin, C. L.; Snow, R. J.; Kashem, M. A.; Wolak, J. P.; King, J.; Kaplita, P. V.; Liu, L. H. 5-Aminomethyl-1 H -benzimidazoles as orally active inhibitors of inducible T-cell kinase (Itk) Bioorg. Med. Chem. Lett. 2008, 18, 5541-5544
16. Moriarty, K. J.; Takahashi, H.; Pullen, S. S.; Khine, H. H.; Sallati, R. H.; Raymond, E. L.; Woska, J. R., Jr.; Jeanfavre, D. D.; Roth, G. P.; Winters, M. P.; Qiao, L.; Ryan, D.; DesJarlais, R.; Robinson, D.; Wilson, M.; Bobko, M.; Cook, B. N.; Lo, H. Y.; Nemoto, P. A.; Kashen, M. A.; Wolak, J. P.; White, A.; Magolda, R. L.; Tomczuk, B. Discovery, SAR and X-ray structure of 1 H -benzimidazole-5-carboxylic acid cyclohexyl-methyl-amides as inhibitors of inducible T-cell kinase (Itk) Bioorg. Med. Chem. Lett. 2008, 18, 5545-5549
17. Riether, D.; Zindell, R.; Kowalski, J. A.; Cook, B. N.; Bentzien, J.; De Lombaert, S.; Thomson, D.; Kugler, S. Z., Jr.; Skow, D.; Martin, L. S.; Raymond, E. L.; Khine, H. H.; O'Shea, K.; Woska, J. R., Jr.; Jeanfavre, D.; Sellati, R.; Ralph, K. L. M.; Ahlberg, J.; Labissiere, G.; Kashem, M. A.; Pullen, S. S.; Takahashi, H. 5-Aminomethylbenzimidazoles as potent ITK antagonists Bioorg. Med. Chem. Lett. 2009, 19, 1588-1591
18. Lo, H. Y.; Bentzien, J.; Fleck, R. W.; Pullen, S. S.; Khine, H. H.; Woska, J. R.; Kugler, S. Z.; Kashen, M. A.; Takahashi, H. 2-Aminobenzimidazoles as potent ITK antagonists: trans -stilbene-like moieties targeting the kinase specificity pocket Bioorg. Med. Chem. Lett. 2008, 18, 6218-6221
19. Charrier, J. D.; Miller, A.; Kay, D. P.; Brenchley, G.; Twin, H. C.; Collier, P. N.; Ramaya, S.; Keily, S. B.; Durrant, S. J.; Knegtel, R. M.; Tanner, A. J.; Brown, K.; Curnock, A. P.; Jimenez, J. M. Discovery and structure-activity relationships of 3-aminopyrid-2-ones as potent and selective interleukin-2 inducible T-cell kinase (Itk) inhibitors J. Med. Chem. 2011, 54, 2341-2350
20. Herdemann, M.; Weber, A.; Jonveaux, J.; Jonveaux, J.; Schwoebel, S.; Heit, I. Optimization of ITK inhibitors through successive design cycles Bioorg. Med. Chem. Lett. 2011, 21, 1852-1856
21. McLean, L. R.; Zhang, Y.; Zaidi, N.; Bi, X.; Wang, R.; Dharanipragada, R.; Jurcak, J. G.; Gillespy, T. A.; Zhao, Z.; Musick, K. Y.; Choi, Y. M.; Barrague, M.; Peppard, J.; Smicker, M.; Duguid, M.; Parkar, A.; Fordham, J.; Kominos, D. X-ray crystallographic structure-based design of selective thienopyrazole inhibitors of interleukin-2-inducible tyrosine kinase Bioorg. Med. Chem. Lett. 2012, 22, 3296-3300
22. Zapf, C. W.; Gerstenberger, B. S.; Xing, L.; Limburg, D. C.; Anderson, D. R.; Caspers, N.; Han, S.; Aulabaugh, A.; Kurumbail, R.; Shakya, S.; Li, X.; Spaulding, V.; Czerwinski, R. M.; Seth, N.; Medley, Q. G. Covalent inhibitors of interleukin-2 inducible T cell kinase (Itk) with nanomolar potency in a whole blood assay J. Med. Chem. 2012, 55, 10047-10063
23. Pastor, R. M.; Burch, J. D.; Magnuson, S.; Ortwine, D. O.; Chen, Y.; De La Torre, K.; Ding, X.; Eigenbrot, C.; Johnson, A.; Liimatta, A.; Liu, Y.; Shia, S.; Wang, X.; Wu, L. C.; Pei, Z. Discovery and optimization of indazoles as potent and selective interleukin-2 inducible T cell kinase (ITK) inhibitors Bioorg. Med. Chem. Lett. 2014, 24, 2448-2452
24. Harling, D. J.; Deakin, A. M.; Campos, S.; Grimley, R.; Chaudry, L.; Nye, C.; Polyakova, O.; Bessant, C. M.; Barton, N.; Somers, D.; Barrett, J.; Graves, R. H.; Hanns, L.; Kerr, W. J.; Solari, R. Discovery of Novel Irreversible Inhibitors of Interleukin (IL)-2-inducible tyrosine kinase (Itk) by targeting cysteine 442 in the ATP pocket J. Biol. Chem. 2013, 288, 28195-28206
25. Alder, C. M.; Ambler, M.; Campbell, A. J.; Champigny, A. C.; Deakin, A. M.; Harling, J. D.; Harris, C. A.; Longstaff, T.; Lynn, S.; Maxwell, A. C.; Mooney, C. J.; Scullion, C.; Singh, O. M. P.; Smith, I. E. D.; Somers, D. O.; Tame, C. J.; Wayne, G.; Wilson, C.; Woolven, J. M. Identification of a novel and selective series of Itk inhibitors via a template-hopping strategy ACS Med. Chem. Lett. 2013, 4, 948-952
26. MacKinnon, C. H.; Lau, K.; Burch, J. D.; Chen, Y.; Dines, J.; Ding, X.; Eigenbrot, C. E.; Heifetz, A.; Jaochico, A.; Johnson, A.; Kraemer, J.; Kruger, S.; Krulle, T. M.; Liimatta, M.; Ly, J.; Maghames, R.; Montalbetti, C. A. G. N.; Ortwine, D. F.; Perez-Fuertes, Y.; Shia, S.; Stein, D. B.; Trani, G.; Vaidya, D. G.; Wang, X.; Bromidge, S. M.; Wu, L. C.; Pei, Z. Structure-based design and synthesis of potent benzothiazole inhibitors of Interleukin-2 inducible T cell kinase (Itk) Bioorg. Med. Chem. Lett. 2013, 23, 6331-6335
27. Burch, J. D.; Lau, K.; Barker, J. J.; Brookfield, F.; Chen, Y.; Chen, Y.; Eigenbrot, C.; Ellebrandt, C.; Ismaili, M. H. A.; Johnson, A.; Kordt, D.; MacKinnon, C. H.; McEwan, P. A.; Ortwine, D. F.; Stein, D. B.; Wang, X.; Winkler, D.; Yuen, P.-W.; Zhang, Y.; Zarrin, A. A.; Pei, Z. Property- and structure-guided discovery of a tetrahydroindazole series of interleukin-2 inducible T-cell kinase inhibitors J. Med. Chem. 2014, 57, 5714-5727
28. Charrier, J.-D.; Knegtel, R. M. Advances in the design of ITK inhibitors Expert Opin. Drug Discovery 2013, 8, 369
29. Wang, F.; Luo, T.; Hu, J.; Wang, Y.; Krishnan, H. S.; Jog, P. V.; Ganesh, S. K.; Prakash, G. K. S.; Olah, G. A. Synthesis of gem -difluorinated cyclopropanes and cyclopropenes: trifluoromethylsilane as difluorocarbene source Angew. Chem., Int. Ed. 2011, 50, 7153-7157
30. Mitsonobu, O. The use of diethyl azodicarboxylate and triphenylphosphine in synthesis and transformation of natural products Synthesis 1981, 1-28
31. Zabierek, A. A.; Konrad, K. M.; Haidle, A. M. A practical two-step synthesis of 1-alkyl-4-aminopyrazoles Tetrahedron Lett. 2008, 49, 2996-2998
32. Alvarez-Write, M. T.; Satici, H.; Eilel, E. L.; White, P. S. Stereochemistry of addition of organometallic reagents to 2-acyloxanes and 2-acylthianes J. Indian. Chem. Soc. 1999, 76, 617-629
33. Thai, K.-M.; Ecker, G. F. Predictive Models for hERG Channel Blockers: Lignad-Based and Structure-Based Approaches Curr. Med. Chem. 2007, 14, 3003-3026
34. For an example, see Olaharski, A.; Gonzaludo, N.; Bitter, H.; Goldstein, D.; Kirchner, S.; Uppal, H.; Kolaja, K. PLoS Comput. Biol. 2009, 5, e1000446