α-((Tetronoyl)oxy)- and α-((tetramoyl)oxy)methyl ketone inhibitors of the interleukin-1β converting enzyme (ICE)

Bioorganic and Medicinal Chemistry Letters

Volumn 7, Issue 1, 1997, Pages 41-46

  Graybill, Todd L ^a,b   Prouty, Catherine P ^a,c   Speier, Gary J ^a,d   Hoyer, Denton ^a,e   Dolle, Roland E ^a,f   Helaszek, Carla T ^a   Ator, Mark A ^a,g   Uhl, Joanne ^a,h   Strasters, Joost ^a,i  

^a Sanofi Winthrop Inc   (United States)

^b 3 Dimensional Pharmaceuticals   (United States)

^c R W JOHNSON PHARMACEUTICAL RES I   (United States)

^d TEMPLE UNIVERSITY   (United States)

^e NOVARTIS PHARMA AG   (Switzerland)

^f PHARMACOPEIA INC   (United States)

^g CEPHALON INC   (United States)

^h SANOFI   (France)

ⁱ Nycomed Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ASPARTIC ACID DERIVATIVE; INTERLEUKIN 1BETA CONVERTING ENZYME; INTERLEUKIN 1BETA CONVERTING ENZYME INHIBITOR; TETRONIC ACID DERIVATIVE;

ARTICLE; DRUG DESIGN; DRUG STABILITY; DRUG SYNTHESIS; ENZYME INHIBITION; IN VITRO STUDY; STRUCTURE ACTIVITY RELATION;

EID: 0031033587     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(96)00574-4     Document Type: Article

References (35)

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12. a of 3.5, cathepsin B inactivation rates range some 200-fold. Potency is also dependent on the type and pattern of aryl substitution in the aspartyl α-((aryl)acyloxy)methyl ketone class of ICE inhibitor, unpublished observation. In constrast, Thornberry et al. (Tables 1 and 2, ref 4a) have shown that the second order rate of inactivation is independent of the leaving group pKa for certain tri- and tetrapeptide aspartyl α-((aryl)acyloxy)methyl ketones analogs.
13. Dolle, R. E.; Singh, J.; Rinker, J.; Hoyer, D.; Prasad, C. V.C.; Graybill, T. L.; Salvino, J. M.; Helaszek, C. T.; Miller, R. E.; Ator, M. A. J. Med. Chem. 1994, 37, 3863.
14. Dolle, R. E.; Singh, J.; Whipple, D.; Osifo, I. K.; Speier, G.; Graybill, T. L.; Gregory, J. S; Harris, A. L.; Helaszek, C. T.; Miller, R. E.; Ator, M. A. J. Med Chem. 1995, 38, 220.
15. (a) Hlasta, D. J.; Ackerman, J. H.; Court, J. J.; Farrell, R. P.; Johnson, J. A.; Kofron, J. L.; Robinson, D. T.; Talomie, T. G.; Dunlap, R. P.; Franke, C. A. J. Med. Chem. 1995, 38, 4687.
16. (b) Refer to ref 10a for the structural details of our initial set of 25 leaving groups.
17. 2O: C, 59.90; H, 6.13; N, 6.55. Found: C, 59.52; H, 5.81; N, 6.70.
18. Ramage, R.; Griffiths, G. J.; Shutt, F. E.; Sweeney, J. N. A. J. Chem. Soc. Perkins Trans. 1 1984, 1539.
19. Hayes, L. J.; Stanners, A. H. J. Chem. Soc. 1956, 4103.
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21. Fuerstenwerth, H. Ger. Patent 3525109, 1987; Chem. Abstr. 1985, 106, 103815.
22. This decision tree is a manual method to apply Hansch type principles without the use of statistical procedures and computers. See Topliss, J. G. J. Med. Chem. 1977, 20, 463 and references therein.
23. Uhl, J.; Krasney, P.; Brophy, L.; Arnold, R.; Dolle, R.; Helaszek, C.; Miller, R.; Gilman, S.; Ator, M. Inflammation Research 1995, 44, S211.
24. a 3.4 (Charton, J. Org. Chem. 1965, 974)).
25. O-, S-, and N-based nucleophiles are known to react with alkyl tetronates and other vinylogous carbonates under a variety of nonphysiological conditions (see Shandala, M. Y.; Ayoub, M. T.; Mohammad, M. J. J. Heterocycl. Chem. 1984, 21, 1753; Croxall, W. J.; Freimiller, L. R.; Shropshire, Y. J. Am. Chem. Soc. 1950, 72, 4275; De Benneville, P. L.; Macartney, J. H. J. Am. Chem. Soc. 1950, 72, 3725).
26. O-, S-, and N-based nucleophiles are known to react with alkyl tetronates and other vinylogous carbonates under a variety of nonphysiological conditions (see Shandala, M. Y.; Ayoub, M. T.; Mohammad, M. J. J. Heterocycl. Chem. 1984, 21, 1753; Croxall, W. J.; Freimiller, L. R.; Shropshire, Y. J. Am. Chem. Soc. 1950, 72, 4275; De Benneville, P. L.; Macartney, J. H. J. Am. Chem. Soc. 1950, 72, 3725).
27. O-, S-, and N-based nucleophiles are known to react with alkyl tetronates and other vinylogous carbonates under a variety of nonphysiological conditions (see Shandala, M. Y.; Ayoub, M. T.; Mohammad, M. J. J. Heterocycl. Chem. 1984, 21, 1753; Croxall, W. J.; Freimiller, L. R.; Shropshire, Y. J. Am. Chem. Soc. 1950, 72, 4275; De Benneville, P. L.; Macartney, J. H. J. Am. Chem. Soc. 1950, 72, 3725).
28. The buffer stability of analog 14 was not determined since the geminal disubstitution was poorly tolerated by the enzyme (see Table 2).
29. 50 10 μM).
30. n2 displacement of leaving group is the rate-determining step in ICE inactivation for a series of tetrapeptide α-((aryl)acyloxy)- and (aryloxy)methyl ketones (see ref 4a).
31. Graybill, T. L.; Dolle, R. E.; Helaszek, C. T.; Miller, R. E.; Ator, M. A. Int. J. Peptide Protein Res. 1994, 44, 173.
32. Inhibitor 20 has not been tested in a cell-based assay.
33. 6b
34. 9
35. Dolle, R. E.; Prouty, C. P.; Prasad, C.V.C.; Cook, E.; Saha, A.; Ross, R. M.; Salvino, J.; Helaszek, C. T.; Ator, M. A. J. Med. Chem. 1996, 39, 2438.