First dual M3 antagonists-PDE4 inhibitors: Synthesis and SAR of 4,6-diaminopyrimidine derivatives

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 7, 2006, Pages 1834-1839

  Provins, Laurent ^a   Christophe, Bernard ^b   Danhaive, Pierre ^a   Dulieu, Jacques ^a   Durieu, Véronique ^a   Gillard, Michel ^a   Lebon, Florence ^a   Lengelé, Sébastien ^a   Quéré, Luc ^a   Van Keulen, Berendjan ^a  

^a UCB   (Belgium)

^b R and D   (Belgium)

Author keywords

COPD; Muscarinic receptor(s); Phosphodiesterase; Pyrimidine

Indexed keywords

MUSCARINIC RECEPTOR BLOCKING AGENT; PHOSPHODIESTERASE IV INHIBITOR; PYRIMIDINE DERIVATIVE; UCB 101333 3; UNCLASSIFIED DRUG; 3',5' CYCLIC NUCLEOTIDE PHOSPHODIESTERASE; ENZYME INHIBITOR; MUSCARINIC M3 RECEPTOR; PHOSPHODIESTERASE IV;

ANIMAL TISSUE; ANTIINFLAMMATORY ACTIVITY; ARTICLE; CHEMICAL PROCEDURES; CONTROLLED STUDY; DRUG ACTIVITY; DRUG SYNTHESIS; HUMAN; HUMAN CELL; NONHUMAN; STRUCTURE ACTIVITY RELATION; CHEMISTRY; DRUG ANTAGONISM; SYNTHESIS;

ANIMALIA;

3',5'-CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE; ENZYME INHIBITORS; MUSCARINIC ANTAGONISTS; PYRIMIDINES; RECEPTOR, MUSCARINIC M3; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 33144462084     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.01.006     Document Type: Article

References (30)

1. P.J. Barnes Pharmacol. Rev. 56 2004 515
2. E. Rand Sutherland, and R.J. Martin J. Allergy Clin. Immunol. 112 2003 819
3. R. Buhl, and S.G. Farmer Proc. Am. Thorac. Soc. 2 2005 83
4. P.J. Barnes, and T.T. Hansel Lancet 364 2004 985
5. L.E. Donnelly, and D.F. Rogers Drugs 63 2003 1973
6. G. Krishna, V. Sankaranarayanan, and R.K. Chitkara Expert Opin. Invest Drugs 13 2004 255
7. P.J. Barnes Chest 117 2000 10S
8. J.F. Donohue Chest 126 2004 125S
9. S.I. Rennard Lung Biol. Health Dis. 145 2000 159
10. C.A. Panning, and M. DeBisschop Pharmacotherapy 23 2003 183
11. K.M. Hvizdos, and K.L. Goa Drugs 62 2002 1195
12. M.D. Houslay, P. Schafer, and K.Y. Zhang J. Drug Discovery Today 10 2005 1503 and references cited therein
13. J.O. Odingo Expert Opin. Ther. Patents 15 2005 773
14. B.J. Lipworth Lancet 365 2005 167
15. A. Hatzelmann, and C. Schudt J. Pharm. Exp. Ther. 297 2001 267
16. D.S. Bundschuh, M. Eltze, J. Barsig, L. Wollin, A. Hatzelmann, and R.J. Beume Pharm. Exp. Ther. 297 2001 280
17. L. Provins, B. Christophe, P. Danhaive, J. Dulieu, V. Durieu, M. Gillard, F. Lebon, S. Lengelé, L. Quéré, and B.J. van Keulen Sci. Pharm. 73 2005 S180
18. H. Gershon, R. Braun, A. Scala, and R. Rodin J. Med. Chem. 7 1964 808
19. G. Biagi, I. Giorgi, O. Livi, V. Scartoni, and A. Lucacchini Farmaco 52 1997 61
20. J.P. Beck, A.G. Arvanitis, M.A. Curry, J.T. Rescinito, L.W. Fitzgerald, P.J. Gilligan, R. Zaczek, and G.L. Trainor Bioorg. Med. Chem. Lett. 9 1999 967
21. C. Chen, R. Dagnino, E.B. De Souza, D.E. Grigoriadis, and C.Q. Huang J. Med. Chem. 39 1996 4358
22. R.J. Chorvat, R. Bakthavatchalam, J.P. Beck, P.J. Gilligan, and R.G. Wilde J. Med. Chem. 42 1999 833
23. 3H]cAMP as a substrate.
24. 3H]N-methylscopolamine performed in CHO cell membranes expressing recombinant human receptors.
25. 3CN. See also: S. Ong, H. Liu, and C. Pidgeon J. Chromatogr. A 728 1996 113
26. Separation of the diastereoisomers has been performed via chiral chromatography (Daicel Chiralpak AD column).
27. All titrations were performed using a GlpKa™ (Sirius, Forest Row, UK) and done in aqueous solution or methanol-water mixture with 0.15 M KCL at 25°C using standardized 0.5 M HCL titrant.
28. CCDC 290973 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
29. CCDC 290974 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
30. B. Christophe, F. Lelubre, L. Provins, M. Peck, and R. Massingham The Pharmacologist 44 2002 A227