Synthesis and SAR of highly potent and selective dopamine D 3-receptor antagonists: 1H-Pyrimidin-2-one derivatives

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 3, 2006, Pages 490-494

  Geneste, Hervé ^a   Backfisch, Gisela ^a   Braje, Wilfried ^a   Delzer, Jürgen ^a   Haupt, Andreas ^a   Hutchins, Charles W ^b   King, Linda L ^a   Kling, Andreas ^a   Teschendorf, Hans Jürgen ^a   Unger, Liliane ^a   Wernet, Wolfgang ^a  

^a ABBOTT GMBH AND CO KG   (Germany)

^b ABBOTT LABORATORIES   (United States)

Author keywords

1H Pyrimidin 2 ones; Atypical antipsychotics; Dopamine D3 receptor antagonists

Indexed keywords

3,4,4A,10B TETRAHYDRO 4 PROPYL 2H,5H [1]BENZOPYRANO[4,3 B][1,4]OXAZIN 9 OL; A 437203; A 690344; DOPAMINE 3 RECEPTOR BLOCKING AGENT; PYRIMIDINONE DERIVATIVE; UNCLASSIFIED DRUG;

ANALYTICAL ERROR; ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; DRUG EFFICACY; DRUG POTENCY; DRUG SELECTIVITY; DRUG SYNTHESIS; IN VIVO STUDY; MOLECULAR MODEL; NONHUMAN; RAT; SOCIAL INTERACTION; STRUCTURE ACTIVITY RELATION;

ANIMALS; BENZOPYRANS; DOPAMINE ANTAGONISTS; MODELS, CHEMICAL; OXAZINES; PYRIMIDINONES; RATS; RECEPTORS, DOPAMINE D3; STRUCTURE-ACTIVITY RELATIONSHIP;

ANIMALIA;

EID: 29544431769     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.10.068     Document Type: Article

References (29)

1. A. Hackling, R. Ghosh, S. Perachon, A. Mann, H.-D. Höltje, C.G. Wermuth, J.-C. Schwartz, W. Sippl, P. Sokoloff, and H. Stark J. Med. Chem. 46 2003 3883 and references cited therein
2. Unger, L.; Ladona, F. J. G.; Wernet, W.; Sokoloff, P.; Wicke, K. M.; Gross, G. Poster, 32nd Annual Meeting of the Society for Neuroscience, Orlando, FL, Nov 2-7, 2002; Society for Neuroscience: Washington, DC, 2002; Abstr. 894.5.
3. Drescher, K. U.; Ladona, F. J. G., Teschendorf, H. J.; Traut, M.; Unger, L.; Wicke, K. M.; Weddige, F. K.; Freeman, A. S.; Gross, G. Poster, 32nd Annual Meeting of the Society for Neuroscience, Orlando, FL, Nov 2-7, 2002; Society for Neuroscience: Washington, DC, 2002; Abstr. 894.6.
4. C.R. Ashby, Y. Minabe, and G. Stemp J. Pharmacol. Exp. Ther. 294 2000 1166
5. C. Reavill, S.G. Taylor, and M.D. Wood J. Pharmacol. Exp. Ther. 294 2000 1154
6. The preparation of the building blocks mentioned, typical procedures and assay setup are described in DE 10311065, 2004; Chem. Abstr. 2004, 141, 296038.
7. 2=H in Scheme 1), the yield remained moderate (46%) due to simultaneous O-alkylation (12%).
8. The preparation of the building block QH (Scheme 1) is described in DE 19735410, 1999; Chem. Abstr. 1999, 130, 182482.
9. D.J. Brown, and T.-C. Lee Aust. J. Chem. 21 1968 243
10. W.D. Jones, E.W. Huber, J.M. Grisan, and R.A. Schnettler J. Heterocycl. Chem. 24 1987 1221
11. Y. Gong, and H.W. Pauls Synlett 2002 829
12. T. Benneche, and K. Undheim Acta Chem. Scand. B 38 1984 505
13. Preparation analog to: Z. Andriamialisoa, A. Valla, D. Cartier, and R. Labia Helv. Chim. Acta 85 2002 2926
14. R.W. Lamon J. Heterocycl. Chem. 5 1968 837
15. 8 or by treatment of the urea derivative with phosphorus pentasulfide according to B. Lal, A.N. Dohadwalla, N.K. Dadkar, A. D'Sa, and N.J. de Souza J. Med. Chem. 27 1984 1470
16. D.J. Fenick, H.S. Carr, and D.E. Falvey J. Org. Chem. 60 1995 624
17. K. Wicke, and J. Garcia-Ladona Eur. J. Pharmacol. 424 2001 85
18. Geneste, H.; Backfisch, G.; Braje, W.; Delzer, J.; Haupt, A.; Hutchins, C. W.; King, L. L.; Lubisch, W.; Steiner, G.; Teschendorf, H.-J.; Unger, L.; Wernet, W. Bioorg. Med. Chem. Lett., in press.
19. C. Hutchins Endocr. J. 2 1994 7
20. Hutchins, C. In Structure and Function of 7TM Receptors;
21. Schwartz, T. W., Hjorth, S. A., Sandholm Kastrup, J., Ed.; Alfred Benzon Symposium 39, Munksgaard: Copenhagen, 1996; pp 213-226.
22. 1
23. The calculation of polar surface area is based on fragment contributions: P. Ertl, B. Rohde, and P. Selzer J. Med. Chem. 43 2000 3714
24. Seventy-five binding assays comprising receptors, ion channels, and enzymes: www.cerep.com.
25. Measured in % recovery of parent after 1 h incubation at 37°C with liver microsomes (rat and human) in the presence of NADPH.
26. P. Artursson Crit. Rev. Ther. Drug Carrier Syst. 8 1991 105
27. A.R. Hilgers, R.A. Conradi, and P.S. Burton Pharm. Res. 7 1990 902
28. Adapted from T. Kagaya, M. Yonaga, Y. Furuya, T. Hashimoto, J. Kuroki, and Y. Nishizawa Brain Res. 721 1996 229
29. Jongen-Rêlo, A. L.; Drescher, K. U.; Teschendorf, H. J.; Rueter, L. E.; Unger, L.; Gross, G; Schoemaker, H. Poster, 34th Annual Meeting of the Society for Neuroscience, San Diego, CA, October 23-27, 2004; Society for Neuroscience: Washington, DC, 2004; Abstr. 350.2.