Pyridone-based peptidomimetic inhibitors of interleukin-1β-converting enzyme (ICE)

Bioorganic and Medicinal Chemistry Letters

Volumn 7, Issue 10, 1997, Pages 1337-1342

  Semple, Graeme ^a   Ashworth, Doreen M ^a   Baker, Graham R ^a   Batt, Andrzej R ^a   Baxter, Andrew J ^a   Benzies, David W M ^a   Elliot, Lucy H ^a   Evans, D Michael ^a   Franklin, Richard J ^a   Hudson, Peter ^a   Jenkins, Paul D ^a   Pitt, Gary R ^a   Rooker, David P ^a   Sheppard, Andrew ^a   Szelke, Michael ^a   Yamamoto, Satoshi ^b   Isomura, Yasuo ^b  

^a Chilworth Research Centre   (United Kingdom)

^b Yamanouchi Inst Drug Discov Res   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

INTERLEUKIN 1BETA CONVERTING ENZYME; INTERLEUKIN 1BETA CONVERTING ENZYME INHIBITOR; RECOMBINANT ENZYME;

ARTICLE; CONTROLLED STUDY; DRUG DESIGN; DRUG SYNTHESIS; ENZYME INHIBITION; HUMAN; IN VITRO STUDY; REACTION ANALYSIS; STRUCTURE ACTIVITY RELATION;

EID: 0031579968     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(97)00220-5     Document Type: Article

References (16)

1. Thornberry N.A., Bull H.G., Calaycay J.R., Chapman K.T., Howard A.D., Kosturas M.J., Millar D.K., Molineaux S.M., Weidner J.R., Aunins J., Elliston K.O., Ayala J.M., Casano F.J., Chin J., Ding G.J.-F., Egger L.A., Gaffney E.P., Limjuco G., Palyha O.C., Raju S.M., Rolando A.M., Salley J.P., Yamin T.-T., Lee T.D., Shively J.E., MacCross M., Mumford R.A., Schmidt J.A., Tocci M.J. Nature. 356:1992;768-774.
2. IL-1β has been implicated in the pathogenesis of several inflammatory disorders. Dinarello, C.A. Blood 1991, 77, 1627-1652.
3. Alnemri E.S., Livingston D.J., Nicholson D.W., Salvesen G., Thornberry N.A., Wong W.W., Yuan J.-Y. Cell. 87:1996;171.
4. Steller H. Science. 267:1995;1445.
5. a) Chapman, K.T. Bioorg. Med. Chem. Lett. 1992, 2, 613-618.
6. b) Mjalli, A.M.M.; Chapman, K.T.; MacCross, M.; Thornberry, N.A. Bioorg. Med. Chem. Lett. 1993, 3, 2689-2695.
7. a) Dolle, R.E.; Hoyer, D.; Prasad, C.V.C.; Schmidt, S.J.; Helaszek, C.T.; Miller, R.E.; Ator, M.A. J. Med. Chem. 1994, 37, 563-564.
8. b) 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, 3863-3866.
9. c) 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, 220-222.
10. Mjalli A.M.M., Zhao J.J., Chapman K.T., Thornberry N.A., Peterson E.P., MacCross M., Hagmann W.K. Bioorg. Med. Chem. Lett. 5:1995;1409-1414.
11. Irreversible inhibition was characterised by the lack of substrate turnover following pre-incubation of enzyme and inhibitor. With all the compounds described herein as reversible inhibitors, the progress curves were independent of the order of addition of enzyme or inhibitor to the substrate/buffer mixture.
12. Pyridones have been used previously as Val-Pro mimetics in the design of inhibitors of human leukocyte elastase see: Brown, F.J.; Andisik, D.W.; Bernstein, P.R.; Bryant, C.B.; Ceccarelli, C.; Damewood, J.R. Jr.; Edwards, P.D.; Earley, R.A.; Feeney, S.; Green, R.C.; Gomes, B.C.; Kosmider, B.J.; Krell, R.D.; Shaw, A.; Steelman, G.B.; Thomas, R.M.; Vacek, E.P.; Veale, C.A.; Tuthill, P.A.; Warner, P.; Williams, J.C.; Wolanin, D.J.; Woolson, S.A. J. Med. Chem. 1994, 37, 1259-1261.
13. Irreversible pyrimidone-based inhibitors of ICE have been described recently: Dolle, R.E.; Prouty, C.P.; Prasad, C.V.C.; Cook, E.; Saha, A.; Ross, T.M.; Salvino, J.M.; Helaszek, C.T.; Ator, M.A. J. Med. Chem. 1996, 39, 2438-2440.
14. Damewood J.R. Jr., Edwards P.D., Feeney S., Gomes B.C., Steelman G.B., Tuthill P.A., Williams J.C., Warner P., Woolson S.A., Wolanin D.J., Veale C.A. J. Med. Chem. 37:1994;3303-3312.
15. Kazmaier U. J. Org. Chem. 59:1994;6667-6670.
16. Inhibition assays using recombinant human ICE (hrICE) were performed according to the methods described in except that AcTyrValAlaAspAFC (AFC = 7-amino-4-trifluoromethylcoumarin) was used in place of AcTyrValAlaAspAMC (AMC = 7-amino-4-methylcoumarin) as the fluorogenic substrate. This substrate had excitation and emission wavelengths at 395nm and 515nm respectively. Ki values were determined using standard Dixon Plots and are ± S.E.M.