5-HT2C antagonists based on fused heterotricyclic templates: Design, synthesis and biological evaluation

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 2, 2007, Pages 424-427

  Hamprecht, Dieter ^a   Micheli, Fabrizio ^a   Tedesco, Giovanna ^a   Donati, Daniele ^a   Petrone, Marcella ^a   Terreni, Silvia ^a   Wood, Martyn ^b  

^a GSK   (Italy)

^b GLAXOSMITHKLINE   (United Kingdom)

Author keywords

5 HT2c receptor antagonists; 5 HT2c receptors; Antidepressant; Anxiolytic agent; Fused rings; Serotonin receptors; Vinylic and aromatic double bonds

Indexed keywords

CARBON; SEROTONIN 2 ANTAGONIST; DYES, REAGENTS, INDICATORS, MARKERS AND BUFFERS; HETEROCYCLIC COMPOUND; SEROTONIN 2A RECEPTOR; SEROTONIN 2B RECEPTOR; SEROTONIN 2C RECEPTOR; SEROTONIN ANTAGONIST;

ARTICLE; BIOAVAILABILITY; CHEMICAL BOND; CONFORMATION; DRUG ACTIVITY; DRUG CLEARANCE; DRUG DESIGN; DRUG STRUCTURE; DRUG SYNTHESIS; NONHUMAN; RAT; RECEPTOR AFFINITY; RECEPTOR BINDING; ALKYLATION; ANIMAL; CHEMICAL STRUCTURE; DRUG EFFECT; HUMAN; MALE; STRUCTURE ACTIVITY RELATION; SYNTHESIS;

ALKYLATION; ANIMALS; BIOLOGICAL AVAILABILITY; DRUG DESIGN; HETEROCYCLIC COMPOUNDS; HUMANS; INDICATORS AND REAGENTS; MALE; MODELS, MOLECULAR; MOLECULAR CONFORMATION; RATS; RECEPTOR, SEROTONIN, 5-HT2A; RECEPTOR, SEROTONIN, 5-HT2B; RECEPTOR, SEROTONIN, 5-HT2C; SEROTONIN ANTAGONISTS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 33846075785     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.10.034     Document Type: Article

References (18)

1. See for example,. Nutt D.J., Forshall S., Bell C., Rich A., Sandford J., Nash J., and Argyropoulos S. Eur. Neuropsychopharmacol. 9 Suppl. 3 (1999) S81
2. Murphy D.L., Andrews A.M., Wichems C.H., Li Q., Tohda M., and Greenberg B. J. Clin. Psychiatry 59 Suppl. 15 (1998) 4
3. Serretti A., Artioli P., and De Ronchi D. Expert Opin. Ther. Targets 8 (2004) 15
4. Kahn R.S., and Wetzler S. Biol. Psychiatry 30 (1991) 1139
5. Kennett G.A., Wood M.D., Bright F., Cilia J., Piper D.C., Gager T., Thomas D., Baxter G.S., Forbes I.T., Ham P., and Blackburn T.P. Br. J. Pharmacol. 117 (1996) 427
6. Kennett G.A., Wood M.D., Bright F., Trail B., Riley G., Holland V., Avenell K.Y., Stean T., Upton N., Bromidge S., Forbes I.T., Brown A.M., Middlemiss D.N., and Blackburn T.P. Neuropharmacology 36 (1997) 609
7. Micheli F., Pasquarello A., Tedesco G., Hamprecht D., Bonanomi G., Checchia A., Jaxa-Chamiec A., Damiani F., Davalli S., Donati D., Gallotti C., Petrone M., Rinaldi M., Riley G., Terreni S., and Wood M. Bioorg. Med. Chem. Lett. 16 (2006) 3906
8. Schrodinger Inc., Portland. http://www.schrodinger.com.
9. Gasteiger J., Rudolph C., and Sadowski J. Tetrahedron Computer Methodology 3 (1990) 537
10. Sadowski J., Rudolph C., and Gasteiger J. Anal. Chim. Acta 265 (1992) 233
11. 2C receptors, in analogy to the procedure described in. Wood M.D., Reavill C., Trail B., Wilson A., Stean T., Kennett G.A., Lightowler S., Blackburn T.P., Thomas D., Gager D.L., Riley G., Holland V., Bromidge S.M., Forbes I.T., and Middlemiss D.N. Neuropharmacology 41 (2001) 186
12. Gruda I. Can. J. Chem. 50 (1972) 18
13. Bunce R.A., Randall M.H., and Applegate K.G. Org. Prep. Proced. Int. 34 (2002) 493
14. 3; or EDCI) provided only low yields.
15. The research complied with national legislation and with company policy on the Care and Use of Animals and with related codes of practice.
16. For iv administration, the compound was dissolved in 25% (v/v) PEG400 aq containing 5% (v/v) DMSO at a concentration of 0.5 mg free base/mL and administered (2 mL/kg) as a bolus to male rats (n = 3) at a nominal dose level of 1 mg free base/kg. Brain penetration was evaluated at 1 h. For po administration, the compound was dissolved in Methocel 0.5% w/v containing 5% DMSO at a concentration of 0.6 mg free base/mL and administered (5 mL/kg) by gavage to male rats (n = 3) at a nominal dose level of 3 mg free base/kg.
17. Thiele J., and Schneider J. Justus Liebigs Ann. Chem. 369 (1909) 287
18. b values determined according to,. Jerman J.C., Brough S.J., Gager T., Wood M., Coldwell M.C., Smart D., and Middlemiss D.N. Eur. J. Pharmacol. 414 (2001) 23 with the exception that the receptors were expressed in HEK293 cells as described in Ref. 8