Discovery of a novel series of nonacidic benzofuran EP1 receptor antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 14, 2011, Pages 4343-4348

  Allan, Amanda C ^a   Billinton, Andy ^a   Brown, Susan H ^a   Chowdhury, Anita ^a   Eatherton, Andrew J ^a   Fieldhouse, Charlotte ^a   Giblin, Gerard M P ^a   Goldsmith, Paul ^a   Hall, Adrian ^a,b   Hurst, David N ^a   Naylor, Alan ^a   Rawlings, D Anthony ^a   Sime, Mairi ^a,c   Scoccitti, Tiziana ^a   Theobald, Pamela J ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

^b European Knowledge Centre   (United Kingdom)

^c BEATSON INSTITUTE FOR CANCER RESEARCH   (United Kingdom)

Author keywords

CNS penetration; EP1 antagonist; Pain; Scaffold hopping

Indexed keywords

6 [2 [5 CHLORO 2 (2,4 DIFLUOROBENZYLOXY)PHENYL] 1 CYCLOPENTENYL] 2 PYRIDINECARBOXYLIC ACID; BENZOFURAN DERIVATIVE; CELECOXIB; GSK345931A; PROSTAGLANDIN E RECEPTOR 1; PROSTAGLANDIN RECEPTOR BLOCKING AGENT; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL TISSUE; ARTICLE; BINDING AFFINITY; CHRONIC PAIN; DRUG ACTIVITY; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG EFFICACY; DRUG PENETRATION; DRUG RECEPTOR BINDING; DRUG SOLUBILITY; DRUG STABILITY; LIPOPHILICITY; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; BENZOFURANS; CELL LINE; DISEASE MODELS, ANIMAL; DOGS; DRUG EVALUATION, PRECLINICAL; PAIN; RATS; RECEPTORS, PROSTAGLANDIN E, EP1 SUBTYPE; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 79959915590     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2011.05.047     Document Type: Article

References (21)

1. A. Hall, A. Billinton, and G.M.P. Giblin Curr. Opin. Drug Discovery Dev. 10 2007 597 and references cited therein
2. G.M.P. Giblin, R.A. Bit, S.H. Brown, H.M. Chaignot, A. Chowdhury, I.P. Chessell, N.M. Clayton, T. Coleman, A. Hall, B. Hammond, D.N. Hurst, A.D. Michel, A. Naylor, R. Novelli, T. Scoccitti, D. Spalding, S.P. Tang, A.W. Wilson, and R. Wilson Bioorg. Med. Chem. Lett. 17 2007 385
3. A. Hall, S.H. Brown, C. Budd, N.M. Clayton, G.M.P. Giblin, P. Goldsmith, T.G. Hayhow, D.N. Hurst, A. Naylor, D.A. Rawlings, T. Scoccitti, A.W. Wilson, and W.J. Winchester Bioorg. Med. Chem. Lett. 19 2009 497
4. A. Hall, S. Atkinson, S.H. Brown, I.P. Chessell, A. Chowdhury, N.M. Clayton, T. Coleman, G.M.P. Giblin, R.J. Gleave, B. Hammond, M.P. Healy, M.R. Johnson, A.D. Michel, A. Naylor, R. Novelli, D.J. Spalding, S.P. Tang, and R.J. Wilson Bioorg. Med. Chem. Lett. 16 2006 3657
5. S.C. McKeown, A. Hall, G.M.P. Giblin, O. Lorthioir, R. Blunt, X.Q. Lewell, R.J. Wilson, S.H. Brown, A. Chowdhury, T. Coleman, S.P. Watson, I.P. Chessell, A. Pipe, N. Clayton, and P. Goldsmith Bioorg. Med. Chem. Lett. 16 2006 4767
6. A. Hall, A. Billinton, S.H. Brown, N.M. Clayton, A. Chowdhury, G.M.P. Giblin, P. Goldsmith, T.G. Hayhow, D.N. Hurst, I.R. Kilford, A. Naylor, B. Passingham, and L. Winyard Bioorg. Med. Chem. Lett. 18 2008 3392
7. A. Hall, A. Billinton, A.K. Bristow, S.H. Brown, A. Chowdhury, L. Cutler, G.M.P. Giblin, P. Goldsmith, T.G. Hayhow, I.R. Kilford, A. Naylor, B. Passingham, and D.A. Rawlings Bioorg. Med. Chem. Lett. 18 2008 4027
8. D.F. Veber, S.R. Johnson, H.-Y. Cheng, B.R. Smith, K.W. Ward, and K.D. Kopple J. Med. Chem. 45 2002 2615
9. M.R. Attwood, I. Churcher, R.M. Dunsdon, D.N. Hurst, and P.S. Jones Tetrahedron Lett. 32 1991 811
10. Gibson, M.; Hall, A.; Hurst, D.N.; Rawlings, D.A. WO2007113289A1.
11. M.J. Iadarola, J. Douglass, O. Civelli, and J.R. Naranjo Brain Res. 455 1988 205
12. C.H. Hay, M.A. Trevethick, A. Wheeldon, J.S. Browers, and J.S. De Belleroche Neuroscience 7 1997 843
13. i of 5 mL/min/g liver corresponds to approximately 60% turnover after 30 min incubation
14. E.S. Kostewicz, M. Wunderlich, U. Brauns, R. Becker, T. Bock, and J.B. Dressman J. Pharm. Pharmacol. 56 2005 43
15. E. Galia, E. Nicolaides, D. Horter, R. Löbenberg, C. Reppas, and J.B. Dressman Pharm. Res. 15 1998 698
16. C.E. Castro, E.J. Gaughan, and D.C. Owsley J. Org. Chem. 31 1966 4071
17. C.E. Castro, R. Havlin, V.K. Honwad, A. Malte, and S. Mojé J. Am. Chem. Soc. 91 1969 6464
18. Eatherton, A. J.; Giblin, G. M. P.; Gibson, M.; Hurst, D. N. WO2008098978A2/A3.
19. Note the brain concentrations were measured in only three rats, mean brain concentration = 3.969 μM. The average blood concentration from the same three rats was 2.339 μM. Thus, this equates to a Br:Bl of 1.70, n = 3.
20. S.G. Summerfield, A.J. Stevens, L. Cutler, M. del Carmen Osuna, B. Hammond, S-P. Tang, A. Hersey, D.J. Spalding, and P. Jeffrey J. Pharmacol. Exp. Ther. 316 2006 1282
21. A.W. Wilson, S.J. Medhurst, C.I. Dixon, N.C. Bontoft, L.A. Winyard, K.T. Brackenborough, J. De Alba, C.J. Clarke, M.J. Gunthorpe, G.A. Hicks, C. Bountra, D.S. McQueen, and I.P. Chessell Eur. J. Pain 10 2006 537