A novel 5-[1,3,4-oxadiazol-2-yl]-N-aryl-4,6-pyrimidine diamine having dual EGFR/HER2 kinase activity: Design, synthesis, and biological activity

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 17, 2008, Pages 4896-4899

  Hughes, Terry V ^a   Xu, Guozhang ^a   Wetter, Steven K ^a   Connolly, Peter J ^a   Emanuel, Stuart L ^a   Karnachi, Prabha ^a   Pollack, Scott R ^a   Pandey, Niranjan ^a   Adams, Mary ^a   Moreno Mazza, Sandra ^a   Middleton, Steven A ^a   Greenberger, Lee M ^a  

^a JOHNSON AND JOHNSON PHARMACEUTICAL RESEARCH AND DEVELOPMENT   (United States)

Author keywords

EGFR; HER1; HER2; Intramolecular hydrogen bond; Kinase; Oxadiazole; Pyrimidine; Quinazoline mimic; Restricted rotation

Indexed keywords

5 [ 1,3,4 OXADIAZOL 2 YL] N ARYL 4,6 PYRIMIDINE DIAMINE; DIAMINE DERIVATIVE; EPIDERMAL GROWTH FACTOR RECEPTOR 2; EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; BIOLOGICAL ACTIVITY; CONTROLLED STUDY; DRUG ACTIVITY; DRUG DESIGN; DRUG SYNTHESIS; ENZYME INHIBITION; HUMAN; HUMAN CELL;

CELL LINE; DIAMINES; DRUG DESIGN; HELA CELLS; HUMANS; OXADIAZOLES; PROTEIN BINDING; PYRIMIDINES; RECEPTOR, EPIDERMAL GROWTH FACTOR; RECEPTOR, ERBB-2; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 49849098785     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.07.057     Document Type: Article

References (16)

1. Cohen P. Nat. Rev. (2002) 309
2. Mendelsohn J., and Baselga J. Oncogene (2000) 6550
3. Slamon D.J., Clark G.M., Wong S.G., Levin W.J., Ullrich A., and McGuire R.L. Science (1987) 177
4. Klijn J.G., Berns P.M., Schmitz P.I., and Foekens J.A. Endocr. Rev. (1992) 3
5. Xu G., Searle L.L., Hughes T.V., Beck A.K., Connolly P.J., Abad M.C., Neeper M.P., Struble G.T., Springer B.A., Emanuel S.L., Gruninger R.H., Pandey N., Adams M., Moreno-Mazza S., Fuetnes-Pesquera A.R., Middleton S.A., and Greenberger L.A. Bioorg. Med. Chem. Lett. (2008) 3495
6. Gomtsyan A., Didomenico S., Lee C., Matulenko M.A., Kim K., Kowaluk E.A., Wismer C.T., Mikusa J., Yu H., Kohlhaas K., Jarvis M.F., and Bhagwat S.S. J. Med. Chem. (2002) 3639
7. Our process group has recently disclosed a detailed discussion of their efforts to optimize this reaction:. Choudhury A., Chen H., Nilsen C.N., and Sorgi K.L. Tetrahedron Lett. (2008) 102
8. Kumemura T., Choshi T., Hirata A., Sera M., Takahashi Y., Nobuhiro J., and Hibino S. Heterocycles (2003) 13
9. Compound 8j was prepared as previously described: Xu, G.; Lee, L.; Connolly, P. J.; Middleton, S. A.; Emanuel, S. L.; Hughes, T. V.; Abad, M. C.; Karnachi, P. S.; Wetter, S. K.; WO 2007081630, 2007.
10. Watjen F., Baker R., Engelstoff M., Herbert R., MacLeod A., Knight A., Merchant K., Moseley J., Saunders J., Swain C.J., Wong E., and Springer J.P. J. Med. Chem. (1989) 2282
11. ProteinPrep module, Schrodinger, New York, 2005.
12. Glide 3.5, Schrodinger, New York, 2005.
13. Friesner R.A., Banks J.L., Murphy R.B., Halgren T.A., Klicic J.J., Mainz D.T., Repasky M.P., Knoll E.H., Shaw D.E., Shelley M., Perry J.K., Francis P., and Shenkin P.S. J. Med. Chem. (2004) 1739
14. No scaling factors were applied to the van der Waals radii. Default settings were used for all the remaining parameters. The top 20 poses based on Glidescore were energy-minimized with Macromodel using the OPLS-AA, and the refined poses were reranked using Glidescore.
15. The energies were calculated using the OPLS_2005 force field with a constant dielectric of 1.0 using the Macromodel module.
16. Choi Y., Ishikawa H., Velcicky J., Elliott G.I., Miller M.M., and Boger D.L. Org. Lett. (2005) 4539