The synthesis and biological evaluation of a novel series of indole PDE4 inhibitors I

Bioorganic and Medicinal Chemistry Letters

Volumn 8, Issue 14, 1998, Pages 1867-1872

  Hulme, Christopher ^a   Moriarty, Kevin ^a   Miller, Bruce ^a   Mathew, Rose ^a   Ramanjulu, Mercy ^a   Cox, Paul ^b   Souness, John ^b   Page, Ken M ^b   Uhl, Joanne ^a   Travis, Jeffrey ^a   Huang, Fu Chih ^a   Labaudiniere, Richard ^a   Djuric, Stevan W ^a  

^a SANOFI   (France)

^b Rhone Poulenc Rorer Ctrl Research   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLIC NUCLEOTIDE PHOSPHODIESTERASE; PHOSPHODIESTERASE INHIBITOR; PICLAMILAST; ROLIPRAM; TUMOR NECROSIS FACTOR ALPHA;

ANIMAL EXPERIMENT; ANIMAL MODEL; AREA UNDER THE CURVE; ARTICLE; BINDING SITE; DRUG HYDROLYSIS; DRUG STRUCTURE; INTRAVENOUS DRUG ADMINISTRATION; MALE; MOUSE; NONHUMAN; ORAL DRUG ADMINISTRATION; STRUCTURE ACTIVITY RELATION; SYNTHESIS;

3',5'-CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE; ANIMALS; BIOLOGICAL AVAILABILITY; DRUG EVALUATION; INDOLES; MICE; PHOSPHODIESTERASE INHIBITORS; PYRROLIDINONES; ROLIPRAM; STRUCTURE-ACTIVITY RELATIONSHIP;

ANIMALIA;

EID: 0032555249     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(98)00324-2     Document Type: Article

References (28)

1. 1. For two reviews see (a) Palfreyman, M. N. Drugs of the Future 1995, 20, 793.
2. (b) Torphy, T. J.; Livi, G. P.; Christensen, S. B. DN & P 1993, 6, 203.
3. 2. Beavo, J. A.; Conti, M.; Heaslip, R. J. Mol. Pharmacol. 1994, 46, 399.
4. 3. (a) Verghese, M. W.; McConnenell, R. T.; Strickland, A. B.; Gooding, R. C.; Stimpson, S. A.; Yarnall, D. P.; Taylor, J. D.; Furdon, P. J. J. Pharmacol. Exp. Ther. 1995, 272, 1313.
5. (b) Renz, H.; Gong, J-H.; Schmidt, A.; Nain, M.; Gemsa, D. J. Immunol. 1988, 141, 2388.
6. (c) Sullivan, P. J.; Bekir, S.; Jaffar, Z.; Page, C. P.; Jeffrey, P. K.; Costello, J. Lancet 1994, 343, 1006.
7. (d) Raeburn, D.; Underwood, S. L.; Lewis, S. A.; Woodman, V. R.; Battram, C. H.; Tomkinson, A.; Sharma, S.; Jordan, R.; Souness, J. E.; Webber, S. E.; Karlsson, J-A. Brit. J. Pharmacol. 1994, 113,1423.
8. (e) Waage, A.; Haltensen, A.; Espink, T. Lancet 1987, 1, 355.
9. (f) Matsuura, A.; Ashizawa, N.; Asakura, N.; Kumonaka, T.; Aotsuka, T.; Hase, T.; Shimizu, C.; Kurihara, T.; Kobayashi, F. Biol. Pharm. Bull. 1994, 17, 498.
10. (g) Williams, R. D.; Feldmann, M.; Maini, R. N. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 9783.
11. 4. (a) Hulme, C.; Poli, G.B.; Huang, F-C.; Souness, J.E.; Djuric, S.W. Bioorg. Med. Chem. Lett. 1998, 8, 175.
12. (b) Hulme, C.; Moriarty, K.; Huang, F-C.; Mason, J.; McGarry, D.; Labaudiniere, R.; Souness, J.; Djuric, S. Bioorg. Med. Chem. Lett. 1998, 8, 399.
13. 5. (a) Kleinman, E. F.; Campbell, E.; Giordano, L. A.; Cohan, V.L.; Jenkinson, T. H.; Cheng, J. B.; Shirley, J. T.; Pettipher, E. R.; Salter, E. D.; Hibbs, T. A.; DiCapua, F. M.; Bordner, J. J. Med. Chem. 1998, 41, 266.
14. (b) Stafford, J. A.; Veal, J. M.; Feldman, P. L.; Valvano, N. L.; Baer, P. G.; Brackeen, M. F.; Brawley, E. S.; Connolly, K. M.; Domanico, P. L.; Han, B.; Rose, D. A.; Rutkowske, R. D.; Sekut, L.; Stimpson, S. A.; Strickland, A. B.; Verghese, M. W. J. Med. Chem. 1995, 38, 4972.
15. (c) Masamune, H.; Cheng, J. B.; Cooper, K.; Eggler, J. F.; Marfat, A.; Marshall, S. C.; Shirley, J. T.; Tickner, J. E.; Umland, J. P.; Vazquez, E. Bioorg. Med. Chem. Lett. 1995, 5, 1965.
16. (d) Marivet, M. C.; Bourguignon, J-J.; Lugnier, C.; Mann, A.; Stoclet, J-C.; Wermuth, C-G. J. Med. Chem. 1989, 32, 1450.
17. 6. (a) Ashton, M. J.; Cook, D. C.; Fenton, G.; Karlsson, J-A.; Palfreyman, M. N.; Raeburn, D.; Ratcliff, A. J.; Souness, J. E.; Thurairatnam, S.; Vicker, N. J. Med. Chem. 1994, 37, 1696.
18. 7. (a) A series of PDE4 inhibitors containing an indazole replacement for the 3-methoxy-4-cyclopentoxy 'rolipram-like' motif has recently been reported : Marfat, A.; WO9742174-A1, 1997.
19. (b) Stafford, J. A.; Feldman, P. L.; Marron, B. E.; Schoenen, F. J.; Valvano, N. L.; Unwalla, R. J.; Domanico, P. L.; Brawley, E. S.; Leesnitzer, M. A.; Rose, D. A.; Dougherty, R. W. Bioorg. Med. Chem. Lett. 1994, 4, 1855
20. 8. Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. Tetrahedron Lett. 1989, 30, 1927.
21. 9. Orfanopoulos, M.; Smonou, I. Synth. Comm. 1988, 18, 833.
22. 3H] rolipram in a guinea pig brain membrane binding assay. See Schmeichen, R.; Schneider, H. H.; Watchtel, H. Psychopharmacology 1990, 102, 17.
23. 3H] rolipram in a guinea pig brain membrane binding assay. See Schmeichen, R.; Schneider, H. H.; Watchtel, H. Psychopharmacology 1990, 102, 17.
24. 3H] rolipram in a guinea pig brain membrane binding assay. See Schmeichen, R.; Schneider, H. H.; Watchtel, H. Psychopharmacology 1990, 102, 17.
25. 11. For TNF-α production in vivo Male, Balb/c mice (20-25 g, Harlan-Sprague Dawley, Inc., Indianaopolis, IN) were used. For evaluation of test compounds, compounds were administered by oral gavage in a suspension (0.5% methylcellulose/0.2% Tween-80 vehicle) 4 h prior to challenge with lipopolysaccharide (LPS). TNF-α production was elicited by an intraperitoneal injection of LPS (E. coli 055:B5, Sigma Chemical Co., St. Louis, MO) at a dose of 30 μg/mouse. Ninety minutes after LPS injection, mice were anesthetized with Isoflurane and blood collected by cardiac puncture. The whole blood was allowed to clot at room temperature and serum was prepared by centrifugation at 500 g for 10 min. TNF-α levels in the serum were measured by a mouse TNF-α ELISA (Genzyme Corp., Cambridge, MA).
26. 5 cells/well and allowed to adhere for 2 h. Test compounds were added followed by addition of 0.01% Staphylococcus aureus (IgGSORB, The Enzyme Center, Malden, MA) to activate the cells. The cells were then incubated overnight and the media was collected and assayed for TNF-α by ELISA (Human TNF-α Duoset, Genzyme Corp., Cambridge, MA).
27. 13. Christensen, S. B.; Guider, A.; Forster, C. J.; Gleason, J. G.; Bender, P. E.; Karpinski, J. M.; DeWolf, W. E.; Barnette, M. S.; Underwood, D. C.; Griswold, D. E.; Cieslinski, L. B.; Burman, M.; Bochnowicz, S.; Osborn, R. R.; Manning, C. D.; Grous, M.; Hillegas, L. M.; Bartus, J.; Ryan, M. D.; Eggleston, D. S.; Haltiwanger, R. C.; Torphy, T. J. J. Med. Chem., 1998, 41, 821.
28. 2 asphyxiation, and blood obtained by cardiac puncture.