Synthesis and biological activity of a series of tetrasubstituted- imidazoles as P2X7 antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 16, 2010, Pages 4951-4954

  Gleave, Robert J ^a   Walter, Daryl S ^a   Beswick, Paul J ^a   Fonfria, Elena ^a   Michel, Anton D ^a   Roman, Shilina A ^a   Tang, Sac Pham ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

Author keywords

Ion channel; P2X7; Pain

Indexed keywords

IMIDAZOLE DERIVATIVE; PURINERGIC P2X7 RECEPTOR; PURINERGIC RECEPTOR BLOCKING AGENT; NONSTEROID ANTIINFLAMMATORY AGENT; P2RX7 PROTEIN, HUMAN; PURINERGIC P2 RECEPTOR; PURINERGIC P2 RECEPTOR ANTAGONIST; PYRAZOLE; PYRAZOLE DERIVATIVE;

ARTICLE; DRUG RECEPTOR BINDING; DRUG SOLUBILITY; DRUG STABILITY; DRUG SYNTHESIS; HUMAN; IN VITRO SELECTION; NONHUMAN; RAT; REACTION ANALYSIS; STRUCTURE ACTIVITY RELATION; ANIMAL; CHEMISTRY; METABOLISM; SYNTHESIS;

ANIMALS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; HUMANS; IMIDAZOLES; PYRAZOLES; RATS; RECEPTORS, PURINERGIC P2; STRUCTURE-ACTIVITY RELATIONSHIP; PURINERGIC P2 RECEPTOR ANTAGONISTS; RECEPTORS, PURINERGIC P2X7;

EID: 77955420249     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.05.018     Document Type: Article

References (14)

1. A. Colomar, V. Marty, C. Médina, C. Combe, P. Parnet, and T. Amédée J. Biol. Chem. 278 2005 30732
2. J.P. Hughes, J.P. Hatcher, and I.P. Chessell Purinergic Signalling 3 2007 163
3. G. Collo, S. Neidhart, E. Kawashhima, M. Kosco-Vilbois, R.A. North, and G. Buell Neuropharmacology 36 1997 1277
4. I.P. Chessell, J.P. Hatcher, C. Bountra, A.D. Michel, J.P. Hughes, P. Green, J. Egerton, M. Murfin, J. Richardson, W.L. Peck, C.B.A. Grahames, M.A. Casula, Y. Yiangou, R. Birch, P. Anand, and G.N. Buell Pain 114 2005 386
5. J.M. Labasi, N. Petrushova, C. Donovan, S. McCurdy, P. Lira, M.M. Payette, W. Brissette, J.R. Wicks, L. Audoly, and C.A. Gabel J. Immunol. 168 2002 6436
6. R. Romagnoli, P.G. Baraldi, O. Cruz-Lopez, C. Lopez-Cara, D. Preti, P.A. Borea, and S. Gessi Expert Opin. Ther. Targets 12 2008 647
7. L.J. Chambers, A.J. Stevens, A.P. Moses, A.D. Michel, D.S. Walter, D.J. Davies, D.G. Livermore, E. Fonfria, E.H. Demont, M. Vimal, P.J. Theobald, P.J. Beswick, R.J. Gleave, S.A. Roman, and S. Senger Bioorg. Med. Chem. Lett. 2010 10.1016/j.bmcl.2010.03.096
8. 7.4 (ACD) compound 1 = 3.4, compound 2 = 2.2.
9. T.D. Gordon, J. Singh, P.E. Hansen, and B.A. Morgan Tetrahedron Lett. 34 1993 1901
10. 50.
11. S.E. Clarke, and P. Jeffrey Xenobiotica 31 2001 591
12. CYPEX assay using fluorescent substrates. Inhibition of CYP3A4 observed using diethoxyflourescein as a substrate at 1 μM.
13. E. Galia, E. Nicolaides, D. Horter, R. Lobenberg, C. Reppas, and J.B. Dressman Pharm. Res. 15 1998 698
14. Compound 10 was dosed to three rats orally by gavage at a target dose of 3 mg/kg. The compound was prepared, on the day of dosing, in 1% (w/v) methylcellulose aq at a concentration of 0.6 mg/mL and administered at 5 mL/kg. Serial blood samples were taken from each rat up to 6 h after dose administration. Diluted blood samples were analysed for parent compound by LC/MS/MS. All experiments were performed in accordance with the United Kingdom Animals (Scientific Procedures) Act, 1986 under Project Licence as well as under the review and approval of the GlaxoSmithKline Procedures Review Panel. GlaxoSmithKline safety regulations were adhered to at all times.