Synthesis and SAR of highly potent and selective dopamine D 3-receptor antagonists: Variations on the 1H-pyrimidin-2-one theme

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 7, 2006, Pages 1934-1937

  Geneste, Hervé ^a   Amberg, Wilhelm ^a   Backfisch, Gisela ^a   Beyerbach, Armin ^a   Braje, Wilfried M ^a   Delzer, Jürgen ^a   Haupt, Andreas ^a   Hutchins, Charles W ^b   King, Linda L ^a   Sauer, Daryl R ^b   Unger, Liliane ^a   Wernet, Wolfgang ^a  

^a ABBOTT GMBH AND CO KG   (Germany)

^b ABBOTT LABORATORIES   (United States)

Author keywords

Atypical antipsychotics; Dopamine D3 receptor antagonists

Indexed keywords

AMINE; DOPAMINE 2 RECEPTOR; DOPAMINE 3 RECEPTOR; DOPAMINE 3 RECEPTOR BLOCKING AGENT; PYRIMIDINONE DERIVATIVE; UREA;

ARTICLE; BRAIN; COMPREHENSION; CONTROLLED STUDY; DOG; DRUG BIOAVAILABILITY; DRUG PENETRATION; DRUG POTENCY; DRUG SELECTIVITY; DRUG SYNTHESIS; EXPECTATION; HUMAN; HUMAN CELL; NONHUMAN; PHARMACOPHORE; PLASMA; RAT; STRUCTURE ACTIVITY RELATION;

BIOLOGICAL AVAILABILITY; DOPAMINE ANTAGONISTS; HUMANS; MICROSOMES, LIVER; PYRIMIDINONES; RECEPTORS, DOPAMINE D3; STRUCTURE-ACTIVITY RELATIONSHIP;

CANIS FAMILIARIS;

EID: 33144464648     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.12.079     Document Type: Article

References (16)

1. 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, November 2-7, 2002; Society for Neuroscience: Washington, DC, 2002; Abs 894.5.
2. 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, November 2-7, 2002; Society for Neuroscience: Washington, DC, 2002; Abs 894.6.
3. H. Geneste, G. Backfisch, W. Braje, J. Delzer, A. Haupt, C.W. Hutchins, L.L. King, A. Kling, H.-J. Teschendorf, L. Unger, and W. Wernet Bioorg. Med. Chem. Lett. 16 2006 490
4. H. Geneste, G. Backfisch, W. Braje, J. Delzer, A. Haupt, C.W. Hutchins, L.L. King, W. Lubisch, G. Steiner, H.-J. Teschendorf, L. Unger, and W. Wernet Bioorg. Med. Chem. Lett. 16 2006 658
5. N.A. Bumagin, and V.V. Bykov Tetrahedron 53 1997 14437
6. For these examples, amine 1 (1.0 equiv) was treated with p-nitrophenylchloroformate (1.1 equiv) and DIEA (1.1 equiv) in a 1:1 mixture of DMA:DCM. The reaction mixture was stirred at ambient temperature for 1 h. To the resulting p-nitrophenyl carbamate solution were added the desired amine (1.25 equiv) and DIEA (2.2 equiv), followed by heating at 55°C overnight. The desired urea was isolated by scavenging the undesired p-nitrophenol by-product with MP-carbonate resin, filtration, concentration, and purification by reverse-phase HPLC.
7. K. Wicke, and J. Garcia-Ladona Eur. J. Pharmacol. 424 2001 85
8. A.J. Leo, and D. Hoekman Perspect. Drug Discovery Des. 18 2000 19
9. The calculation of polar surface area is based on fragment contributions: P. Ertl, B. Rohde, and P. Selzer J. Med. Chem. 43 2000 3714 and references cited therein
10. Measured in % recovery of parent after 1 h incubation at 37 °C with liver microsomes (0.5 mg/mL microsomal protein; rat, dog, and human) in the presence of NADPH.
11. P. Artursson Crit. Rev. Ther. Drug Carrier Syst. 8 1991 105
12. A.R. Hilgers, R.A. Conradi, and P.S. Burton Pharm. Res. 7 1990 902
13. After iv- and po-dosing (2 and 10 mg/kg, respectively).
14. 2
15. 3) of 10)
16. 9