Discovery of aryl aminoquinazoline pyridones as potent, selective, and orally efficacious inhibitors of receptor tyrosine kinase c-Kit

Journal of Medicinal Chemistry

Volumn 51, Issue 11, 2008, Pages 3065-3068

  Hu, Essa ^a   Tasker, Andrew ^a   White, Ryan D ^a   Kunz, Roxanne K ^a   Human, Jason ^a   Chen, Ning ^a   Bürli, Roland ^a   Hungate, Randall ^a   Novak, Perry ^a   Itano, Andrea ^a   Zhang, Xuxia ^a   Yu, Violeta ^a   Nguyen, Yen ^a   Tudor, Yanyan ^a   Plant, Matthew ^a   Flynn, Shaun ^a   Xu, Yang ^a   Meagher, Kristin L ^a   Whittington, Douglas A ^a   Ng, Gordon Y ^a  

^a AMGEN INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DIPYRONE; MITOGEN ACTIVATED PROTEIN KINASE P38; PROTEIN KINASE LCK; PROTEIN TYROSINE KINASE; PROTEIN TYROSINE KINASE INHIBITOR; PYRIDONE DERIVATIVE; QUINAZOLINE DERIVATIVE; STEM CELL FACTOR RECEPTOR; VASCULOTROPIN RECEPTOR 2;

ARTICLE; DRUG ACTIVITY; DRUG SELECTIVITY; DRUG STRUCTURE; ENZYME INHIBITION; FIBROSIS; HISTAMINE RELEASE; HUMAN; LEUKOCYTE ACTIVATION; MAST CELL; NONHUMAN; RODENT; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; CRYSTALLOGRAPHY, X-RAY; HISTAMINE RELEASE; MAST CELLS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-KIT; PYRIDONES; QUINAZOLINES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 44949193784     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm800188g     Document Type: Article

References (43)

1. (a) Garbuzenko, E.; Nagler, A.; Pickholtz, D.; Gillery, P.; Reich, R.; Maquart, F. X.; Levi-Schaffer, F. Human Mast Cells Stimulate Fibroblast Proliferation, Collagen Synthesis and Lattice Contraction: a Direct Role for Mast Cells in Skin Fibrosis. Clin. Exp. Allergy 2002, 32, 237-246.
2. (b) Wang, H.-W.; Tedla, N.; Hunt, J. E.; Wakefield, D.; McNeil, H. P. Mast Cell Acuumulation and Cytokine Expression in the Tight Skin Mouse Model of Scleroderma. Exp. Dermatol. 2005, 14, 295-302.
3. (c) Selman, M.; Thannickal, V. J.; Pardo, A.; Zisman, D. A.; Martinez, F. J.; Lynch, J. P., III. Idiopathic Pulmonary Fibrosis: Pathogenesis and Therapeutic Approaches. Drugs 2004, 64, 405-430.
4. (a) Bachelet, I.; Levi-Schaffer, F. Mast Cells as Effector Cells: A Co-Stimulating Question. Trends Immunol. 2007, 28, 360-365.
5. (b) Kinet, J. P. The Essential Role of Mast Cells in Orchestrating Inflammation. Immunol. Rev. 2007, 217, 5-7.
6. (c) Metz, M.; Maurer, M. Mast Cells: Key Effector Cells in Immune Responses. Trends Immunol. 2007, 28, 234-241.
7. (d) Oh, C. K. Mast Cell Mediators in Airway Remodeling. Chem. Immunol. Allergy 2005, 87, 85-100.
8. (e) Galli, S. J.; Kalesnikoff, J.; Grimbaldeston, M. A.; Piliponsky, A. M.; Williams, C. M. M.; Tsai, M. Mast Cells as "Tunable" Effector and Immunoregulatory Cells: Recent Advances. Annu. Rev. Immunol. 2005, 23, 749-786.
9. (f) Marshall, J. S. Mast-Cell Responses to Pathogens. Nat. Rev.: Immunol. 2004, 4, 787-799.
10. (g) Galli, S. J.; Tsai, M. Mast Cells: Versatile Regulators of Inflammation, Tissue Remodeling, Host Defense and Homeostasis. J. Dermatol. Sci. 2008, 49, 7-19.
11. (h) Caughey, G. H. Mast Cell Tryptases and Chymases in Inflammation and Host Defense. Immunol. Rev. 2007, 217, 141-154.
12. (a) Okayama, Y. Development, Migration, and Survival of Mast Cells. Immunol. Res. 2006, 34, 97-115.
13. (b) Gilfillan, A. M.; Tkaczyk, C. Integrated Signalling Pathways for Mast-Cell Activation. Nat. Rev.: Immunol. 2006, 6, 218-230.
14. (a) Gruber, B. L. Mast Cells in the Pathogenesis of Fibrosis. Curr. Rheumatol. Rep. 2003, 5, 147-153.
15. (b) Edwards, S. T.; Cruz, A. C.; Donnelly, S.; Dazin, P. F.; Schulman, E. S.; Jones, K. D.; Wolters, P. J.; Hoopes, C.; Dolganov, G. M.; Fang, K. C. cKit Immunophenotyping and Metalloproteinase Expression Profiles of Mast Cells in Interstitial Lung Diseases. J. Pathol. 2005, 206, 279-290.
16. (c) Hirata, K.; Sugama, Y.; Ikura, Y.; Ohsawa, M.; Inoue, Y.; Yamamoto, S.; Kitaichi, M.; Ueda, M. Enhanced Mast Cell Chymase Expression in Human Idiopathic Interstitial Pneumonia. Int. J. Mol. Med. 2007, 4, 565-570.
17. (d) Batlle, M.; Pérez-Villa, F.; Lázaro, A.; Garcia-Pras, E.; Ramirez, J.; Ortiz, J.; Orús, J.; Roqué, M.; Heras, M.; Roig, E. Correlation between Mast Cell Density and Myocardial Fibrosis in Congestive Heart Failure Patients. Transplant Proc. 2007, 39, 2347-2349.
18. Yamamoto, T.; Takahashi, Y.; Takagawa, S.; Katayama, I.; Nishioka, K. J. Animal Model of Sclerotic Skin II. Belomycin Induced Scleroderma in Genetically Mast Cell Deficient WBB6F1-WAV(V) Mice. J. Rheumatol. 1999, 12, 2628-2634.
19. (a) C-Kit reviews: Koma, Y.; Ito, A.; Watabe, K.; Hirata, T.; Mizuki, M.; Yokozaki, H.; Kitamura, T.; Kanakura, Y.; Kitamura, Y. Distinct Role for c-Kit Receptor Tyrosine Kinase and SgIGSF Adhesion Molecule in Attachment of Mast Cells to Fibroblasts. Lab. Invest. 2005, 85, 426-435.
20. (b) Hong, L.; Munugalavadla, V.; Kapur, R. cKit-Mediated Overlapping and Unique Functional and Biochemical Outcomes via Diverse Signaling Pathways. Mol. Cell. Biol. 2004, 24, 1401-1410.
21. (c) Boissan, M.; Feber, F.; Guillosson, J. J.; Arock, M. c-Kit and c-Kit Mutations in Mastocytosis and other Hematological Diseases. J. Leukoc. Biol. 2000, 67, 135-148.
22. (d) Lennartsson, J.; Jelacic, T.; Linnekin, R.; Shivakrupa, R. Normal and Oncogenic Forms of the Receptor Tyrosine Kinase Kit. Stem Cells 2005, 23, 16-43.
23. (e) Akin, C.; Fumo, G.; Yavuz, A. S.; Lipsky, P. E.; Neckers, L.; Metcalfe, D. D. A Novel Form of Mastocytosis associated with a Transmembrane c-Kit Mutation and Response to Imatinib. Blood 2004, 103, 3222-3225.
24. (f) Akin, C.; Metcalfe, D. D. The Biology of Kit in Disease and the Application of Pharmacogenetics. J. Allergy Clin. Immunol. 2004, 114, 13-19.
25. (a) Vuorinen, K.; Gao, F.; Oury, T. D.; Kinnula, V. L.; Myllärniemi, M. Imatinib Mesylate Inhibits Fibrogenesis in Asbestos-Induced Interstitial Pneumonia. Exp. Lung Res. 2007, 33, 357-373.
26. (b) Aono, Y.; Nishioka, Y.; Inayama, M.; Ugai, M.; Kishi, J.; Uehara, H.; Izumi, K.; Sone, S. Imatinib as a Novel Antifibrotic Agent in Belomycin-Induced Pulmonary Fibrosis in Mice. Am. J. Respir. Crit. Care Med. 2005, 171, 1279-1285.
27. (a) Beham-Schmid, C.; Apfelbeck, U.; Sill, H.; Tsybrovsky, O.; Hofler, G.; Haas, O. A.; Linkesch, W. Treatment of Chronic Myelogenous Leukemia with Tyrosine Kinase Inhibitor STI571 Results in Marked Regression of Bone Marrow Fibrosis. Blood 2002, 99, 381-383.
28. (b) Bueso-Ramos, C. E.; Cortes, J.; Talpaz, M.; O'Brien, S.; Giles, F.; Rios, M. B.; Medeiros, L. J.; Kantarjian, H. Imatinib Mesylate Therapy Reduces Bone Marrow Fibrosis in Patients with Chronic Myelogenous Leukemia. Cancer 2004, 101, 332-336.
29. (a) Hynes, J. B.; Campbell, J. P. Synthesis of 2-aminoquinazolines from ortho-fluorobenzaldehydes. J. Heterocycl. Chem. 1997, 34, 385-387.
30. (b) DiMauro, E. F.; Newcomb, J.; Nunes, J. J.; Bemis, J. E.; Boucher, C.; Buchanan, J. L.; Buckner, W. H.; Cee, V. J.; Chai, L.; Deak, H. L.; Epstein, L. F.; Faust, T.; Gallant, P.; Geuns-Meyer, S. D.; Gore, A.; Gu, Y.; Henkle, B.; Hodous, B. L.; Hsieh, F.; Huang, X.; Kim, J. L.; Lee, J. H.; Martin, M. W.; Masse, C. E.; McGowan, D. C.; Metz, D.; Mohn, D.; Morgenstern, K. A.; Oliveira-dos-Santos, A.; Patel, V. F.; Powers, D.; Rose, P. E.; Schneider, S.; Tomlinson, S. A.; Tudor, Yan-Yan.; Turci, S. M.; Welcher, A. A.; White, R. D.; Zhao, H.; Zhu, L.; Zhu, X. Discovery of Aminoquinazolines as Potent, Orally Bioavailable Inhibitors of Lck: Synthesis, SAR, and in Vivo Anti-Inflammatory Activity. J. Med. Chem. 2006, 49, 5671-5686.
31. Ishiyama, T.; Murata, M.; Miyaura, N. Palladium(0)-Catalyzed Cross-Coupling Reaction of Alkoxydiboron with Haloarenes: a Direct Procedure for Arylboronic Esters. J. Org. Chem. 1995, 60, 7508-7510.
32. Klapars, A.; Huang, X.; Buchwald, S. L. A General and Efficient Copper Catalyst for the Amidation of Aryl Halides. J. Am. Chem. Soc. 2002, 124, 7421-7428.
33. Manuscript describing the structure-activity relationship of bisamide 2 is in press.
34. 50 = >4.5 μM for all three compounds).
35. Costa, J. J.; Demetri, G. D.; Harrist, T. J.; Dvorak, A. M.; Hayes, D. F.; Merica, E. A.; Menchaca, D. M.; Gringeri, A. J.; Schwartz, L. B.; Galli, S. J. Recombinant Human Stem Cell Factor (Kit Ligand) Promotes Human Mast Cell and Melanocyte Hyperplasia and Functional Activation in Vivo. J. Exp. Med. 1996, 183, 2681-2686.
36. In our rodent model, imatinib decreased histamine release by 88% at 100 mg/kg dose by oral administration.
37. Abad-Zapatero, C.; Metz, J. T. Ligand Efficiency Indices as Guideposts for Drug Discovery. Drug Discovery Today 2005, 10, 464-469.
38. Kerkelä, R.; Grazette, L.; Yacobi, R.; Iliescu, C.; Patten, R.; Beahm, C.; Walters, B.; Shevtsov, S.; Pesant, S.; Clubb, F. J.; Rosenzweig, A.; Salomon, R. N.; Van Etten, R. A.; Alroy, J.; Durand, J.-B.; Force, T. Cardiotoxicity of the Cancer Therapeutic Agent Imatinib Mesylate. Nat. Med. 2006, 12, 908-916.
39. Manning, G.; Whyte, D. B.; Martinez, R.; Hunter, T.; Sudarsanam, S. The Protein Kinase Complement of the Human Genome. Science 2002, 298, 1912-1916.
40. (a) Hoyle, G. W.; Li, J.; Finkelstein, J. B.; Eisenberg, T.; Liu, J. Y.; Lasky, J. A.; Athas, G.; Morris, G. F.; Brody, A. R. Emphysematous Lesions, Inflammation, and Fibrosis in the Lungs of Transgenic Mice Overexpressing Platelet-Derived Growth Factor. Am. J. Pathol. 1999, 154, 1763-1775.
41. (b) Koyama, K.; Hatsushika, K.; Ando, T.; Sakuma, M.; Wako, M.; Kato, R.; Haro, H.; Sugiyama, H.; Hamada, Y.; Ogawa, H.; Nakao, A. Imatinib Mesylate Inhibits Fibrogenesis in Asbestos-Induced Interstitial Pneumonia. Mod. Rheumatol. 2007, 17, 306-10.
42. All kinases were tested at their apparent Km of ATP with respect to 1 μM of peptide substrate at single point. Selectivity was defined as exhibiting greater than 50% of control against target kinases. See Supporting Information for list of kinases screened.
43. Zoog, S. J.; Itano, A.; Trueblood, E.; Pacheco, E.; Ferbas, J.; Ng, G. Y.; Juan, G. unpublished results.