Synthesis and evaluation of novel tricyclic benzo[4.5]cyclohepta[1.2]pyridine derivatives as NMDA/NR2B antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 17, 2009, Pages 5132-5135

  McIntyre, Charles J ^a   McCauley, John A ^a   Bednar, Bohumil ^a   Bednar, Rodney A ^a   Butcher, John W ^a   Claremon, David A ^a   Cunningham, Michael E ^a   Freidinger, Roger M ^a   Gaul, Stanley L ^a   Homnick, Carl F ^a   Koblan, Ken S ^a   Mosser, Scott D ^a   Romano, Joseph J ^a   Liverton, Nigel J ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

NR2B heterocycle

Indexed keywords

ALPHA 1 ADRENERGIC RECEPTOR; N METHYL DEXTRO ASPARTIC ACID; N METHYL DEXTRO ASPARTIC ACID RECEPTOR 2B; N METHYL DEXTRO ASPARTIC ACID RECEPTOR 2B BLOCKING AGENT; N METHYL DEXTRO ASPARTIC ACID RECEPTOR BLOCKING AGENT; POTASSIUM CHANNEL HERG; TRICYCLIC BENZO[4.5]CYCLOHEPTAL[1.2]PYRIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ANNULATION REACTION; ARTICLE; DRUG RECEPTOR BINDING; DRUG SCREENING; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HUMAN CELL; IN VITRO STUDY; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION;

BENZOCYCLOHEPTENES; CELL LINE; ETHER-A-GO-GO POTASSIUM CHANNELS; HUMANS; NEUROTRANSMITTER AGENTS; PYRIDINES; RECEPTORS, N-METHYL-D-ASPARTATE; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 68349128347     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.07.028     Document Type: Article

References (29)

1. Kennedy M.B. Science 290 (2000) 750
2. Muir K.W. Curr. Opin. .Pharmacol. 6 (2006) 53
3. Loftis J.M., and Janowsky A. Pharmacol. Ther. 97 (2003) 55
4. Chazot P.L. Curr. Med. Chem. 11 (2004) 389
5. Gogas K.R. Curr. Opin. Pharmacol. 6 (2006) 68
6. Layton M.E., Kelly III M.J., and Rodzinak K.J. Curr. Top. Med. Chem. 6 (2006) 697
7. McCauley J.A. Exp. Opin. Ther. Pat. 15 (2005) 389
8. Baldessarini R.J. In: Hardman J.G., and Limbird L.E. (Eds). Goodman & Gilman's the Pharmacological Basis of Therapeutics. 10th ed. (2001), McGraw-Hill, New York 451-468 486-490
9. Eisendrath S.J., and Lichtmacher J.E. In: Tierney Jr. L.M., McPhee S.J., and Papadakis M.A. (Eds). Current Medical Diagnosis & Treatment. 45th ed. (2006), Lange Medical Books/McGraw-Hill, New York 1058-1061 1071
10. Dubroeucq M.-C., Stutzmann J.-M., Manfré F., Capet M., and Böhme G.A. In: Mcguire J.L. (Ed). Pharmaceuticals Classes, Therapeutic Agents, Areas of Application Vol. 2 (2000), Wiley, Weinheim 588-605 610-620
11. Details concerning the synthesis and structure-activity-development that lead to the discovery of 1 will be the subject of a future communication.
12. McCauley, J. A.; Butcher, J. W.; Claremon, D. A.; Liverton, N. J.; McIntyre, C. J.; Romano, J. J. WO03084931; Chem. Abstr. 2003, 139, 323441.
13. Vaz R.J., Li Y., and Rampe D. In: King F.D., and Lawton G. (Eds). Progress in Medicinal Chemistry Vol. 43 (2005), Elsevier, Amsterdam 1-18
14. Pearlstein R., Vaz R., and Rampe D. J. Med. Chem. 46 (2003) 2017
15. Calzada B.C., and De Artiñano A.A. Pharmacol. Res. 44 (2001) 195
16. Villani F.J., Daniels P.J.L., Ellis C.A., Mann T.A., and Wang K.-C. J. Heterocycl. Chem. 8 (1971) 73
17. Brenner D.G., Halczenko W., and Shepard K.L. J. Heterocycl. Chem. 19 (1982) 897
18. Christian J., Loebering H.G., and Trinkl K.H. Synthesis 5 (1977) 326
19. Wagner R.B., and Zook H.D. Synthetic Organic Chemistry (1953), Wiley & Sons, New York
20. +, calcd: 311.1179, found: 311.1173.
21. Kiss L., Cheng G., Bednar B., Bednar R.A., Bennett P.B., Kane S.A., McIntyre C.J., McCauley J.A., and Koblan K.S. Neurochem. Int. 46 (2005) 453
22. Mosser S.D., Gaul S.L., Bednar B., Koblan K.S., and Bednar R.A. J. Assoc. Lab. Automat. 8 (2003) 54
23. ® AS 250 × 4.6 mm column, 70% hexane (0.1% diethylamine)/30% ethanol, flow 1.0 mL/min, absorbance 310 nm.
24. Butcher, J. W.; Claremon, D. A.; Connolly, T. M.; Dean, D. C.; Karczewski, J.; Koblan, K. S.; Kostura, M. J.; Liverton, N. J.; Melillo, D. G., PCT Int. Appl. WO 2002005860, 2002.
25. Old D.W., Wolfe J.P., and Buchwald S.L. J. Am. Chem. Soc. 120 (1998) 9722
26. Littke A.F., and Fu G.C. Angew. Chem., Int. Ed. 37 (1998) 3387
27. Marcoux J.-F., Marcotte F.-A., Wu J., Dormer P.G., Davies I.W., Hughes D., and Reider P.J. J. Org. Chem. 66 (2001) 4194
28. Wolfe J.P., and Buchwald S.L. Angew. Chem., Int. Ed. 38 (1999) 2413
29. α1-Adrenergic binding assays were conducted according to:. Greengrass P., and Bremner R. Eur. J. Pharmacol. 55 (1979) 323