Novel and orally active 5-(1,3,4-oxadiazol-2-yl)pyrimidine derivatives as selective FLT3 inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 20, 2008, Pages 5472-5477

  Ishida, Hiroshi ^a   Isami, Shoichi ^a   Matsumura, Tsutomu ^a   Umehara, Hiroshi ^a   Yamashita, Yoshinori ^a   Kajita, Jiro ^a   Fuse, Eiichi ^a   Kiyoi, Hitoshi ^b   Naoe, Tomoki ^c   Akinaga, Shiro ^a   Shiotsu, Yukimasa ^a   Arai, Hitoshi ^a  

^a KYOWA HAKKO KOGYO CO LTD   (Japan)

^b NAGOYA UNIVERSITY SCHOOL OF MEDICINE   (Japan)

^c NAGOYA UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

Author keywords

5 (1,3,4 Oxadiazol 2 yl)pyrimidine; FLT3 inhibitor

Indexed keywords

1,3,4 OXADIAZOLYL; 5 (1,3,4 OXADIAZOL 2 YL)PYRIMIDINE DERIVATIVE; CD135 ANTIGEN; FLT3 PROTEIN INHIBITOR; FUNCTIONAL GROUP; PROTEIN TYROSINE KINASE INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; ARTICLE; CELL LINE; CELL PROLIFERATION; CONTROLLED STUDY; DOSE RESPONSE; DRUG EFFICACY; DRUG STRUCTURE; HUMAN; HUMAN CELL; LEUKEMIA CELL; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION; TUMOR XENOGRAFT;

ADMINISTRATION, ORAL; ANIMALS; CELL LINE, TUMOR; CELL PROLIFERATION; CHEMISTRY, PHARMACEUTICAL; DRUG DESIGN; FMS-LIKE TYROSINE KINASE 3; HUMANS; INHIBITORY CONCENTRATION 50; MICE; MICE, SCID; MODELS, CHEMICAL; NEOPLASM TRANSPLANTATION; OXADIAZOLES; PYRIMIDINES; STRUCTURE-ACTIVITY RELATIONSHIP;

MUS;

EID: 53349162182     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.09.031     Document Type: Article

References (22)

1. Rosnet O., Schiff C., Pebusque M.J., Marchetto S., Tonnelle C., Toiron Y., Birg F., and Birnbaum D. Blood 82 (1993) 1110
2. Lyman S.D., James L., Zappone J., Sleath P.R., Beckmann M.P., and Bird T. Oncogene 8 (1993) 815
3. Kiyoi H., Towatari M., Yokota S., Hamaguchi M., Ohno R., Saito H., and Naoe T. Leukemia 12 (1998) 1333
4. Kiyoi H., Yanada M., and Ozeki K. Int. J. Hematol. 82 (2005) 85
5. Levis M., and Small D. Leukemia 17 (2003) 1738
6. Stone R.M., DeAngelo D.J., Klimek V., Galinsky I., Estey E., Nimer S.D., Grandin W., Lebwohl D., Wang Y., Cohen P., Fox E.A., Neuberg D., Clark J., Gilliland D.G., and Griffin J.D. Blood 105 (2005) 54
7. Knapper S., Burnett A.K., Littlewood T., Kell W.J., Agrawal S., Chopra R., Clark R., Levis M.J., and Small D. Blood 108 (2006) 3262
8. Fiedler W., Serve H., Döhner H., Schwittay M., Ottmann O.G., O'Farrell A.-M., Bello C.L., Allred R., Manning W.C., Cherrington J.M., Louie S.G., Hong W., Brega N.M., Massimini G., Scigalla P., Berdel W.E., and Hossfeld D.K. Blood 105 (2005) 986
9. DeAngelo D.J., Stone R.M., Heaney M.L., Nimer S.D., Paquette R.L., Klisovic R.B., Caligiuri M.A., Cooper M.R., Lecerf J.-M., Karol M.D., Sheng S., Holford N., Curtin P.T., Druker B.J., and Heinrich M.C. Blood 108 (2006) 3674
10. Kiyoi H., Shiotsu Y., Ozeki K., Yamaji S., Kosugi H., Umehara H., Shimizu M., Arai H., Ishii K., Akinaga S., and Naoe T. Clin. Cancer Res. 13 (2007) 4575
11. Brown P., Best D.J., Broom N.J.P., Cassels R., O'Hanlon P.J., Mitchell T.J., Osborne N.F., and Wilson J.M. J. Med. Chem. 40 (1997) 2563
12. Rajapakse H.A., Zhu H., Young M.B., and Mott B.T. Tetrahedron Lett. 47 (2006) 4827
13. Greene T.W., and Wuts P.G.M. Protective Groups in Organic Synthesis (1991), John Wiley and Sons, New York chapter 2, p 41 and references cited therein
14. Landreau C., Deniaud D., Reliquet A., Reliquet F., and Meslin J.C. J. Heterocycl. Chem. 38 (2001) 93
15. Gerstenberger B.S., and Konoperski J.P. J. Org. Chem. 70 (2005) 1467
16. FLT3 kinase assays. To evaluate the kinase inhibitory activities against FLT3 by ELISA, GST-tagged FLT3 cytoplasmic domain and biotinylated poly-(Glu/Tyr 4:1) substrate (CIS bio International) bound to the surface of 96-well assay plates were used. Phosphorylated substrate was bound to anti-phosphotyrosine antibody conjugated to europium. The bound antibody was measured using ARVO (Perkin-Elmer) at excitation/emission of 340/615 nm.
17. Growth inhibition assays. MOLM-13, ML-1, FLT3/Δ599, and FLT3/D835Y were maintained in RPMI1640 with 10% heat-inactivated FBS, 1% penicillin, and 1% streptomycin. HMC-1 cells were maintained in IMEM with 10% heat-inactivated FBS, 0.01% α-thioglycerol, 1% penicillin, and 1% streptomycin. These cell lines were seeded in 96-well culture plates in appropriate media and incubated for 72 h in the presence of test compounds. Cell viability was measured using the cell proliferation reagent WST-1 (Roche) according to the instructions of the manufacture; see also Ref. 19 and 20.
18. 3CN containing internal standard to stop the reaction (samples for quantitative analysis). After centrifugation, the supernatant was analyzed by LC-MS or LC-MS/MS. The values of intrinsic clearance were calculated from percent remaining of the test compound.
19. Cain G.A., and Beck J.P. Heterocycles 55 (2001) 439
20. Daylight version 4.83; Daylight Chemical Information Systems, Inc.: Mission Viejo, CA, 2003.
21. Yamamoto Y., Kiyoi H., Nakano Y., Suzuki R., Kodera Y., Miyawaki S., Asou N., Kuriyama K., Yagasaki F., Shimazaki C., Akiyama H., Saito K., Nishimura M., Motoji T., Shinagawa K., Takeshita A., Saito H., Ueda R., Ohno R., and Naoe T. Blood 97 (2001) 2434
22. Kiyoi H., Ohno R., Ueda R., Saito H., and Naoe T. Oncogene 21 (2002) 2555