Discovery of amido-benzisoxazoles as potent c-Kit inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 18, 2008, Pages 5115-5117

  Kunz, Roxanne K ^a   Rumfelt, Shannon ^a   Chen, Ning ^a   Zhang, Dawei ^a   Tasker, Andrew S ^a   Bürli, Roland ^a   Hungate, Randall ^a   Yu, Violeta ^a   Nguyen, Yen ^a   Whittington, Douglas A ^a   Meagher, Kristin L ^a   Plant, Matthew ^a   Tudor, Yanyan ^a   Schrag, Michael ^a   Xu, Yang ^a   Ng, Gordon Y ^a   Hu, Essa ^a  

^a AMGEN INC   (United States)

Author keywords

c Kit; Mast cells; Receptor tyrosine kinase

Indexed keywords

BENZISOXAZOLE DERIVATIVE; IMATINIB; PROTEIN TYROSINE KINASE; PROTEIN TYROSINE KINASE INHIBITOR; STEM CELL FACTOR RECEPTOR; UNCLASSIFIED DRUG;

ARTICLE; DRUG BINDING; DRUG EFFECT; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TARGETING; ENZYME ACTIVITY; ENZYME REGULATION; GASTROINTESTINAL STROMAL TUMOR; MASTOCYTOSIS; STRUCTURE ACTIVITY RELATION;

AMIDES; COMBINATORIAL CHEMISTRY TECHNIQUES; CRYSTALLOGRAPHY, X-RAY; HUMANS; ISOXAZOLES; MOLECULAR CONFORMATION; MOLECULAR STRUCTURE; P38 MITOGEN-ACTIVATED PROTEIN KINASES; PROTO-ONCOGENE PROTEINS C-KIT; RECEPTOR PROTEIN-TYROSINE KINASES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 51349121840     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.07.111     Document Type: Article

References (20)

1. Nocka K., Majumder S., Chabot B., Ray P., Cervone M., Bernstein A., and Besmer P. Gene Dev.. 3 (1989) 816
2. Heinrich M.C., Blanke C.D., Druker B.J., and Corless C.L. J. Clin. Oncol. 20 (2002) 1692
3. Lennartsson J., Jelacic T., Linnekin D., and Shivakrupa R. Stem Cells 23 (2005) 16
4. Eklund K.K. Immunol. Rev. 217 (2007) 38
5. Marshall J. Nat. Rev. 4 (2004) 787
6. Capdeville R., Buchdunger E., Zimmerman J., and Matter A. Nat. Rev. Drug Discov. 1 (2002) 493
7. c-Kit intrinsic activity was measured by c-Kit-homogeneous time resolved fluorescent assay.
8. Reported activity of Gleevec against c-Kit and p38 was measured internally.
9. Compound 1 was dosed intravenously at 5 mg/kg in rats. After a period of 1, 4, and 8 h, the plasma, bile, and urine were sampled and analyzed for presence of metabolites by LC-MS/MS.
10. Zhu Z., and Espenson J.H. J. Org. Chem. 60 (1995) 1326
11. For in vivo validation of mast-cell activation using structurally distinct chemotypes to that described here, see:. Hu E., Tasker A., White R.D., Kunz R.K., Human J., Chen N., Bürli R., Hungate R., Novak P., Itano A., Zhang X., Yu V., Nguyen Y., Tudor Y., Plant M., Flynn S., Xu Y., Meagher K.L., Whittington D.A., and Ng G.Y. J. Med. Chem. 51 (2008) 3065
12. Chen N., Bürli R.W., Neira S., Hungate R., Zhang D., Yu V., Nguyen Y., Tudor Y., Plant M., Flynn S., Meagher K.L., Lee M.R., Zhang X., Itano A., Schrag M., Xu Y., Ng G.Y., and Hu E. Bioorg. Med. Chem. Lett. 18 (2008) 4137
13. An in vitro metabolite identification study of compound 23 was conducted in rat hepatocytes at 20 μM at 37° C, which produced no evidence of benzisoxazole ring-opening.
14. Angell, R. M.; Baldwin, I. R.; Bamborough, P.; Deboeck, N. M.; Longstaff, T.; Swanson, S. WO2004010995.
15. Unoptimized yields.
16. Manning G., Whyte D.B., Martinez R., Hunter T., and Sudarsanam S. Science 298 (2002) 1912
17. Bunchdunger E., Cioffi C.L., Law N., Stover D., Ohno-Jones S., Druker B.J., and Lydon N.B. J. Pharm. Exp. Ther. 295 (2000) 139
18. PDB deposition code number for the co-crystal structure is 3DTW.
19. Mol C.D., Lim K.B., Vandana Sridhar H.-Z., Chien E.Y.T., Sang B.-C., Nowakowski J., Kassel D.B., Cronin C.N., and McRee D.E. J. Biol. Chem. 278 (2003) 31461
20. Mol C.D., Dougan D.R., Schneider T.R., Skene R.J., Kraus M.L., Schiebe D.N., Snell G.P., Zou H., Sang B.-C., and Wilson K.P. J. Biol. Chem. 279 (2004) 31655