4-Alkylpiperidines related to SR-48968: Potent antagonists of the neurokinin-2 (NK2) receptor

Bioorganic and Medicinal Chemistry Letters

Volumn 8, Issue 14, 1998, Pages 1935-1940

  Jacobs, Robert T ^a   Shenvi, Ashok B ^a   Mauger, Russell C ^a   Ulatowski, Terrance G ^a   Aharony, David ^a   Buckner, Carl K ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

4 (1 HYDROXY 1 ETHYLPROPYL)PIPERIDINE; NEUROKININ 2 RECEPTOR; PIPERIDINE DERIVATIVE; SAREDUTANT; UNCLASSIFIED DRUG;

ARTICLE; BINDING AFFINITY; CARBOXY TERMINAL SEQUENCE; ENANTIOMER; GUINEA PIG; STRUCTURE ACTIVITY RELATION; SYNTHESIS;

ANIMALS; BENZAMIDES; GUINEA PIGS; PIPERIDINES; RECEPTORS, NEUROKININ-2;

CAVIA; CAVIA PORCELLUS; SUS SCROFA;

EID: 0032555192     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(98)00037-7     Document Type: Article

References (23)

1. 1. (a) Regoli, D.; Nantel, F. Biopolymers 1991, 31, 777.
2. (b) Frossard, J.; Advenier, C. Life Sciences 1992, 49, 1941.
3. (c) Leeman, S. E.; Krause, J. E.; Lembeck, F., Eds. Substance P and Related Peptides, Ann. N. Y. Acad. Sci. 1991, 632.
4. 2. (a) Laitinen, L. A.; Heino, M.; Laitinen, A.; Kava T.; Haahtela, T. Am Rev. Respir. Dis. 1985, 131, 599.
5. (b) Devillier, P.; Advenier, C.; Drapeau, G.; Marsac J.; Regoli, D. Br. J. Pharmacol., 1988, 94, 675.
6. (c) Dusser, D. J.; Umeno, E.; Graf, P. D.; Djokic, T.; Borson D. B.; Nadel, J. A. J. Appl. Physiol. 1988, 65, 2585.
7. 3. (a) Frossard N.; Advenier, C. Life Sci. 1991, 49, 1941.
8. (b) Barnes, P. J. Int. Arch. Allergy Appl. Immunol. 1991, 94, 303.
9. (c) Barnes, P. J.; Baraniuk J. N.; Belvisi, M. G. Am. Rev. Respir. Dis. 1991, 144, 1187.
10. (d) Frossard N.; Barnes, P. J. Neuropeptides 1991, 19, 157.
11. (e) Matsuse, T.; Thomson, R. J.; Chen, X.-R.; Salari H.; Schellenberg, R. R. Am. Rev. Respir. Dis. 1991, 144, 368.
12. 4. (a) Emonds-Alt, X.; Vilain, P.; Goulaouic, P.; Proietto, V.; Van Broeck, D.; Advenier, C.; Naline, E.; Neliat, G.; Le Fur, G.; Breliere, J.C. Life Sci. 1992, 50, PL101-106.
13. (b) Advenier, C.; Naline, E.; Toty, L.; Bakdach, H.; Emonds-Alt, X.; Vilain, P.; Breliere, J.-C.; Le Fur, G. Am. Rev. Resp. Dis. 1992, 148, 1177-1181.
14. (c) Emonds-Alt, X.; Advenier, C.; Soubrie, P.; Le Fur, G.; Breliere, J.-C. Drugs of the Future 1995, 20, 701.
15. 5. Emonds-Alt, X.; Proietto, V.; Van Broeck, D.; Vilain, P.; Advenier, C.; Neliat, G.; Le Fur, G.; Breliere, J.-C. Bioorg. Med. Chem. Lett. 1993, 3, 925.
16. 6. Throughout the manuscript, the N-substituent of the piperidine ring is the 3-(3,4-dichlorophenyl)-N-methylbenzamide identical to that found in SR-48968. Unless otherwise noted, all compounds were prepared as mixtures of stereoisomers. (formula presented)
17. 7. Full details for the syntheses of the piperidine derivatives examined in this study can be found in: Jacobs, R. T., Shenvi, A. B., US Patent 5,521,199, May 23, 1996.
18. 8. Aharony, D.; Buckner, C. K.; Ellis, J. L.; Ghanekar, S. V.; Graham, A.; Kays, J. S.; Little, J.; Meeker, S.; Miller, S. C.; Undem B. J.; Waldron, I. R. J. Pharm. Exper. Ther. 1995, 274, 1216.
19. 9. Buckner, C. K.; Ghanekar, S. V.; Kay, J. S.; Krell, R. D.; Fishleder, R. I.; Will, J. A.; Vann, J. M. Annal. N. Y. Acad, Sci. 1991, 629, 340.
20. 10. Kusner, E. J.; Buckner, C. K.; DeHaas, C. J.; Lengel, D. J.; Marks, R. L. Eur. J. Pharm. 1992, 210, 299.
21. B observed for 14 (8.1) as compared to 12 (8.8) is most likely due to the variability of this screen and the low number of tissues used (n = 2).
22. 12. The pH of the reductive amination solution was adjusted to pH 5.5 by addition of glacial acetic acid.
23. 13. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.