Synthesis and SAR of novel 4,5-diarylimidazolines as potent P2X 7 receptor antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 15, Issue 2, 2005, Pages 435-438

  Merriman, Gregory H ^a   Ma, Liang ^a   Shum, Patrick ^a   McGarry, Daniel ^a   Volz, Frank ^a   Sabol, Jeffrey S ^a   Gross, Alexandre ^a   Zhao, Zhicheng ^a   Rampe, David ^a   Wang, Lin ^a   Wirtz Brugger, Friederike ^a   Harris, Bruce A ^a   Macdonald, Douglas ^a  

^a N   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4,5 DIARYLIMIDAZOLINE DERIVATIVE; PURINE P2X7 RECEPTOR; RECEPTOR BLOCKING AGENT; UNCLASSIFIED DRUG;

ARTICLE; DRUG STRUCTURE; DRUG SYNTHESIS; HIGH THROUGHPUT SCREENING; MICROWAVE RADIATION; SOLID; STRUCTURE ACTIVITY RELATION;

ANIMALS; CELL LINE; CRICETINAE; HYDROCARBONS, AROMATIC; IMIDAZOLES; IMIDAZOLINES; INHIBITORY CONCENTRATION 50; RECEPTORS, PURINERGIC P2; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 10644228446     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2004.10.052     Document Type: Article

References (19)

1. F. Di Virgilio Immunol. Today 1995 524
2. A. Suprenant, F. Rassendren, E. Kawashima, R.A. North, and G. Buell Science 272 1996 5262 735
3. 7 antagonists: A. Baxter, J. Bent, K. Bowers, M. Braddock, S. Brough, M. Fagura, M. Lawson, T. McInally, M. Mortimore, M. Robertson, R. Weaver, and P. Webborn Bioorg. Med. Chem. Lett. 13 22 2003 4047
4. L. Alcaraz, A. Baxter, J. Bent, M. Braddock, D. Cladingboel, D. Donald, M. Fagura, C. Laurent, M. Lawson, M. Mortimore, M. McCormick, N. Roberts, and M. Robertson Bioorg. Med. Chem. Lett. 13 22 2003 4043
5. P.G. Baraldi, M.C. Nunez, A. Morelli, S. Falzoni, F. Di Virgilio, and R. Romagnoli J. Med. Chem. 46 2003 1318
6. P.G. Baraldi, R. Romagnoli, M.A. Tabrizi, S. Falzoni, and F. Di Virgilio Bioorg. Med. Chem. Lett. 2000 681
7. R.G. Ravi, S.B. Kertsey, G.R. Dubyak, and K.A. Jacobson Drug Dev. Res. 54 2 2001 75
8. I.P. Chessell, A.D. Michel, and P.P.A. Humphrey Brit. J. Pharmacol. 124 6 1998 1314
9. G. Collo, E. Neidhart, E. Kawashima, M. Kosco-Vilbois, R.A. North, and G. Buell Neuropharmacology 36 9 1997 1277
10. F. Di Virgilio, J.M. Sanz, P. Chiozzi, and S. Falzoni Progr. Brain Res. 120 1999 355
11. D.G. Perregaux, P. McNiff, R. Laliberte, M. Conklyn, and A.G. Gabel J. Immunol. 165 2000 4615
12. M. Solle, J. Labasi, D.G. Perregaux, E. Stam, N. Petrushova, B.H. Koller, R.J. Griffiths, and C.A. Gabel J. Bio. Chem. 276 2001 1 125
13. Resin preparation: To a suspension of 10.0 g (13.2 mmol) of polystyrene-4-nitrophenylcarbonate resin (commercially available Advanced ChemTech 1.32 mmol/g loading) in 150 mL of dichloromethane was added 8.41 g (39.6 mmol) of 1,2-diphenylethylenediamine. The mixture was shaken at room temperature for 12 h then filtered and washed with 4 × 500 mL of dichloromethane and dried in a vacuum oven. Loading was quantitative by UV determination (p-nitrophenol λ 320 nm)
14. D.H. Rich, and J. Singh The Peptides: Analysis, Synthesis, Biology Vol. 1 1979 Academic New York 241
15. I.A. Perillo, M.B. Garcia, F. Niemevz, and L.R. Orelli J. Heterocycl. Chem. 36 1999 105
16. +1 342
17. 50s were calculated using XLfit Version 2.0.9 (ID Business Solutions, Ltd, Surrey, UK) and nonlinear sigmoidal curve fit
18. ATP-stimulated YO-PRO uptake in U373MG cells was abolished by oxidized ATP see: D. Rampe, L. Wang, and G.E. Ringheim J. Neuroimmunol. 147 2004 56
19. Only one enantiomer of 7a (that shown in Table 1) was prepared in this set of compounds, however, given that 7b is also quite potent it is anticipated that the opposite enantiomer of 7a would also be equipotent. Compound 7d was tested only as a racemic mixture