Tricyclic azepine derivatives as selective brain penetrant 5-HT6 receptor antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 20, 2008, Pages 5698-5700

  Trani, Giancarlo ^a   Baddeley, Stuart M ^a   Briggs, Michael A ^a   Chuang, Tsu T ^a   Deeks, Nigel J ^a   Johnson, Christopher N ^a   Khazragi, Abir A ^a   Mead, Tania L ^a   Medhurst, Andrew D ^a   Milner, Peter H ^a   Quinn, Leann P ^a   Ray, Alison M ^a   Rivers, Dean A ^a   Stean, Tania O ^a   Stemp, Geoffrey ^a   Trail, Brenda K ^a   Witty, David R ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

Author keywords

5 HT6 receptor antagonists; CNS penetration; Conformational constraint

Indexed keywords

5 CHLORO N [4 METHOXY 3 (1 PIPERAZINYL)PHENYL] 3 METHYL 2 BENZOTHIOPHENESULFONAMIDE; AZEPINE DERIVATIVE; BENZAZEPINE SULFONAMIDE DERIVATIVE; SEROTONIN 6 ANTAGONIST; TRICYCLIC AZEPINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; BLOOD BRAIN BARRIER; CONFORMATIONAL TRANSITION; DRUG BRAIN LEVEL; DRUG PENETRATION; HYDROGEN BOND; NONHUMAN; RAT; RECEPTOR AFFINITY; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTIDEPRESSIVE AGENTS, TRICYCLIC; BLOOD-BRAIN BARRIER; BRAIN; CHEMISTRY, PHARMACEUTICAL; CYTOCHROME P-450 ENZYME SYSTEM; HUMANS; HYDROGEN BONDING; MICROSOMES; MODELS, CHEMICAL; MOLECULAR CONFORMATION; PROTEIN ISOFORMS; RATS; RECEPTORS, SEROTONIN; SEROTONIN ANTAGONISTS;

EID: 53349146602     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.08.010     Document Type: Article

References (15)

1. Glennon R.A. J. Med. Chem. 46 (2003) 2795
2. Bromidge S.M., Brown A.M., Clarke S.E., Dodgson K., Gager T., Grassam H.L., Jeffrey P.M., Joiner G.F., King F.D., Middlemiss D.N., Moss S.F., Newman H., Riley G.J., Routledge C., and Wyman P. J. Med. Chem. 42 (1999) 202
3. Rogers D.C., and Hagan J.J. Psychopharmacology 158 (2001) 114
4. King M.V., Sleight A.J., Woolley M.L., Topham I.A., Marsden C.A., and Fone K.C.F. Neuropharmacology 47 (2004) 195
5. Reavill C., and Rogers D.C. Curr. Opin. Invest. Drugs 2 (2001) 104
6. Regan, C. M.; Foley, A. G.; Murphy, K. J.; Hirst, W. D.; Gallagher, H. C.; Hagan, J. J.; Upton, N.; Walsh, F. S. Abstracts of Papers, Society for Neuroscience 33rd Annual Meeting, New Orleans, USA, Nov 8-12, 2003; 835.21.
7. Johnson C.N., Roland A., and Upton N. Drug Discov. Today: Therapeut. Strategies 1 (2004) 13
8. Ahmed M., Briggs M.A., Bromidge S.M., Buck T., Campbell L., Deeks N.J., Garner A., Gordon L., Hamprecht D.W., Holland V., Johnson C.N., Medhurst A.D., Mitchell D.J., Moss S.F., Powles J., Seal J.T., Stean T.O., Stemp G., Thompson M., Trail B., Upton N., Winborn K., and Witty D.R. Bioorg. Med. Chem. Lett. 15 (2005) 4867
9. Bromidge, S. M.; Johnson, C. N.; Moss, S. F.; Rahman, S. S.; Witty, D. R. WO2003068751, Chem. Abstr. 2003, 139, 197390.
10. 3) 0.24 (9H, s), 1.47 (9H, s), 2.76 (2H, br s), 2.86-2.88 (2H, m), 3.47-3.51 (4H, m), 7.06 (2H, d), 7.39-7.44 (3H, m), 7.52 (1H, t), 7.75 (2H, d).
11. 6 receptor were treated with the test compound as a solution in DMSO, the agonist 5-HT and ATP. The resulting mixture was incubated to allow the production of cAMP which was then measured using a DiscoveRx HitHunter chemiluminescence cAMP assay kit.
12. 6 receptor antagonist in dimethylsulfoxide (DMSO) was prepared and used to generate a 0.1 mM final working solution in DMSO. This was spiked into 50 mM phosphate buffer (pH 7.4) containing 0.5 mg/mL microsomal protein to give a final incubation concentration of 0.5 μM substrate after the addition of NADP co-factor solution. The solutions were mixed well and pre-incubated for 5 min at ca. 37 °C before the reaction was started with the addition of co-factor. Samples (50 μL) were then taken at 0, 3, 6, 9, 12, 15, 18, 24 and 30 min and at 30 min for the controls into 200 μL acetonitrile containing internal standard. This method was carried out in triplicate. Samples were analysed for parent compound using a specific HPLC/MS/MS method.
13. Crespi C.L., Miller V.P., and Penman B.W. Anal. Biochem. 248 (1997) 188
14. +).
15. 50 value was determined from the dose-response curve. Drug analysis of blood and brain samples using LC/MS/MS allowed direct measurement of brain:blood ratio.