7-Sulfonamido-3-benzazepines as potent and selective 5-HT2C receptor agonists: Hit-to-lead optimization

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 7, 2009, Pages 1871-1875

  Fish, Paul V ^a   Brown, Alan D ^a   Evrard, Edel ^a   Roberts, Lee R ^a  

^a PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United Kingdom)

Author keywords

3 Benzazepine; 5 HT2C receptor; Agonist; Hit to lead; Sulfonamide

Indexed keywords

7 SULFONAMIDO 3 BENZAZEPINE; AZETIDINE DERIVATIVE; CYTOCHROME P450 1A2; CYTOCHROME P450 2D6; DIHYDROBENZOFURAN DERIVATIVE; DILTIAZEM; DOPAMINE 3 RECEPTOR; LORCASERIN; MULTIDRUG RESISTANCE PROTEIN 1; POTASSIUM CHANNEL HERG; PYRROLIDINE DERIVATIVE; SEROTONIN 2A RECEPTOR; SEROTONIN 2B RECEPTOR; SEROTONIN 2C AGONIST; SEROTONIN 2C RECEPTOR; SEROTONIN 6 RECEPTOR; SULFONAMIDE; SULFONE DERIVATIVE; UNCLASSIFIED DRUG; VABICASERIN;

ANIMAL CELL; ARTICLE; CARDIOVASCULAR EFFECT; CELL STRAIN; CELL STRAIN 3T3; CONTROLLED STUDY; DRUG ABSORPTION; DRUG DISTRIBUTION; DRUG EXCRETION; DRUG METABOLISM; DRUG PENETRATION; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HUMAN CELL; LIVER MICROSOME; NONHUMAN; OBESITY; RECEPTOR UPREGULATION; SCHIZOPHRENIA; SEXUAL DYSFUNCTION; STRUCTURE ACTIVITY RELATION; URINE INCONTINENCE;

ANIMALS; BENZAZEPINES; HUMANS; MICE; RECEPTOR, SEROTONIN, 5-HT2C; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES; SWISS 3T3 CELLS;

EID: 61849181565     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.02.071     Document Type: Article

References (32)

1. Alexander S.P.H., Mathie A., and Peters J.A. Brit. J. Pharm. 147 (2006) S6
2. Nilsson B.M. J. Med. Chem. 49 (2006) 4023
3. Dutton A.C., and Barnes N.M. Drug Discovery Today 3 (2006) 577
4. Smith B.M., Thomsen W.J., and Grottick A.J. Expert Opin. Invest. Drugs 15 (2006) 257
5. Wacker D.A., and Miller K.J. Curr. Opin. Drug Dis. Dev. 11 (2008) 438
6. Nichols D.E. Pharmacol. Ther. 101 (2004) 131
7. Villalon C.M., and Centurion D. Naunyn-Schmiedeberg's Arch. Pharmacol. 376 (2007) 45
8. Roth B.L. N. Eng. J. Med. 356 (2007) 6
9. Wang Y., Serradell N., and Bolos J. Drugs Future 32 (2007) 766
10. Smith B.M., Smith J.M., Tsai J.H., Schultz J.A., Gilson C.A., Estrada S.A., Chen R.R., Park D.M., Prieto E.B., Gallardo C.S., Sengupta D., Dosa P.I., Covel J.A., Ren A., Webb R.R., Beeley N.R.A., Martin M., Morgan M., Espitia S., Saldana H.R., Bjenning C., Whelan K.T., Grottick A.J., Menzaghi F., and Thomsen W.J. J. Med. Chem. 51 (2008) 305
11. Thomsen W.J., Grottick A.J., Menzaghi F., Reyes-Saldana H., Espitia S., Yuskin D., Whelan K., Martin M., Morgan M., Chen W., Al-Sham H., Smith B., Chalmers D., and Behan D. J. Pharm. Exp. Ther. 325 (2008) 577
12. Ramamoorthy, P. S.; Beyer, C.; Brennan, J.; Dunlop, J.; Gove, S.; Grauer, S.; Harrison, B. L.; Lin, Q.; Malberg, J.; Marquis, K.; Mazandarani, H.; Piesla, M.; Pulicicchio, C.; Rosenzwieg-Lipson, S.; Sabb, A.-M.; Schechter, L.; Stack, G.; Zhang, J. Abstracts of Papers, 231st ACS National Meeting, Atlanta, GA, United States, March 26-30th, 2006, MEDI-021.
13. 2Cagonists, see:. Bishop M.J., and Nilsson B.M. Expert Opin. Ther. Patents 13 (2003) 1691
14. Lacivita E., and Leopoldo M. Curr. Top. Med. Chem. 6 (2006) 1927
15. Ref. 2.
16. Siuciak J.A., Chapin D.S., McCarthy S.A., Guanowsky V., Brown J., Chiang P., Marala R., Patterson T., Seymour P.A., Swick A., and Iredale P.A. Neuropharmacology 52 (2007) 279
17. Chen, H.; Coffey, S. B.; Lefker, B. A.; Liu, K., WO patent 103511, 2006.
18. Allerton, C.; Andrews, M.; Blagg, J.; Brown, A. D.; Fish, P. V.; Green, M.; Liu, K. 14th SCI-RSC Medicinal Chemistry Symposium; September 23-26th, 2007; Cambridge, UK.
19. Andrews, M.; Blagg, J.; Brennan, P.; Fish, P. V.; Roberts, L.; Storer, R. I.; Whitlock, G. A., WO patent 117169, 2008.
20. Bondinell, W. E.; Ormsbee III, H. S., US patent 4659706, 1987.
21. Maeno, K.; Shimada, I.; Kondoh, Y.; Kadu, H.; Sugasawa, K.; Wanibuchi, F., WO patent 074746, 2002.
22. Smith, B.; Gilson III, C.; Schultz, J.; Estrada, S., WO patent 042491, 2005.
23. Hitchcock S.A., and Pennington L.D. J. Med. Chem. 49 (2006) 1
24. Danilewicz, J.C.; Ellis, D.; Kobylecki, R. J., WO patent 9513274, 1995.
25. Cooper, D. G.; Forbes, I. T.; Garzya, V.; Gribble, A. D.; Lightfoot, A. P.; Payne, A. H.; Walker, G., WO patent 014578, 2005.
26. See: Bondinell, W. E.; Ormsbee III, H. S., EP patent 285287, 1988.
27. Pecherer B., Sunbury R.C., and Brossi A. J. Heterocycl. Chem. 8 (1971) 779
28. Cross, P. E.; Arrowsmith, J. E., EP patent 284384, 1988.
29. Transit performance in the MDCK-mdr1 cell line is commonly used as a model to estimate CNS penetration, see:. Mahar Doan K.M., Humphreys J.E., Webster L.O., Wring S.A., Shampine L.J., Serabjit-Singh C.J., Adkison K.K., and Polli J.W. J. Pharm. Exp. Ther. 303 (2002) 1029
30. 2 receptors in the canine femoral artery. Proceedings of the British Pharmacological Society 2006, 4, 2, 095P; available at http://www.pa2online.org.
31. Fantegrossi W.E., Reissig C.J., Katz E.B., Yarosh H.L., Rice K.C., and Winter J.C. Pharmacol. Biochem. Behav. 88 (2008) 358 and references therein
32. max 51%). Evaluation of 14 in the rat head-twitch model (Ref. 22) at 10 mg/kg (po, n = 8) gave no response and 14 had no significant effect on blood pressure or heart rate during a CV assessment in an anaesthetized dog model up to 0.5 mg/kg (iv infusion over 60 min, n = 4).