Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-05-23
1998-05-26
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514307, 514314, 514326, 514341, 514397, 546146, 546175, 5462747, 546210, 548203, 5483127, 5483147, 5483381, A61K 31415, C07D23361
Patent
active
057565287
ABSTRACT:
The present invention comprises low molecular weight peptidyl compounds that inhibit the farnesyl-protein transferase. Furthermore, these compounds differ from the mono- or dipeptidyl analogs previously described as inhibitors of farnesyl-protein transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.
REFERENCES:
patent: 3280098 (1966-10-01), Otsuka et al.
patent: 4591648 (1986-05-01), Jones et al.
patent: 5043268 (1991-08-01), Stock
patent: 5141851 (1992-08-01), Brown et al.
patent: 5238922 (1993-08-01), Graham et al.
patent: 5326773 (1994-07-01), De Solms et al.
patent: 5340828 (1994-08-01), Graham et al.
patent: 5352705 (1994-10-01), Deana et al.
patent: 5420245 (1995-05-01), Brown et al.
patent: 5439918 (1995-08-01), De Solms et al.
patent: 5504212 (1996-04-01), De Solms et al.
patent: 5534537 (1996-07-01), Ciccarone et al.
Krontiris, T.G., Internal Medicine, 4th ed., 1995, edited by Jay Stein, pp. 699-715.
Brown, T. et al, J.C.S. Chem. Comm. 1981, pp. 648-649.
Colombo, R. et al, J.C.S. Chem. Comm. 1984, pp. 292-293.
Colombo, R. et al, Pept. Proc. Eur. Pept. Symp. 1983, pp. 251-256, online abstract relied upon.
Prior, K.J. et al, J. Labelled Comp. Radiopharm. 1987, 25(3), p. 247.
Patel, D. V. et al, Bioog. Med. Chem. Lett. 1992, 2(9), 1089.
Gibbs, J.B. et al., "Selective Inhibition of Farnesyl-Protein Transferase Blocks Ras Processing in Vivo," The Journal of Biological Chemistry, vol. 268, No. 11, pp. 7617-7620 (1993).
Goldstein, J.L. et al., "Nonfarnesylated Tetrapeptide Inhibitors of Protein Farnesyltransferase," The Journal of Biological Chemistry, vol. 266, No. 24, pp. 15575-15578 (1991).
James, G.L. et al., Benzodiazepine Peptidomimetic BZ-5B Interrupts the MAP Kinase Activation Pathway in H-Ras-transformed Rat-1 Cells, but Not in Untransformed Cells, The Journal of Biological Chemistry, vol. 369, No. 44, pp. 27705-27714 (1994).
James, G.L. et al., "Benzodiazepine Peptidomimetics: Potent Inhibitors of Ras Farnesylation in Animal Cells", Science, vol. 260, pp. 1937-1942 (1993).
Kohl, N.E. et al., "Selective Inhibition of ras-Dependent Transformation by a Farnesyltransferase Inhibitor", Science, vol. 260, pp. 1934-1937 (1993).
Kohl, N.E. et al., "Protein farnesyltransferase inhibitors block the growth of ras-dependent tumors in nude mice", Proc. Natl. Acad. Sci. USA, Med. Sciences, vol. 91, pp. 9141-9145 (1994).
Pompliano, D.L., "Steady-State Kinetic Mechanism of Ras Farnesyl:Protein Transferase", Biochemistry, vol. 31, pp. 3800-3807 (1992).
James, G., et al., Polylysine and CVIM Sequences of K-RasB Dictate Specificity of Prenylation and Confer Resistance to Benzodiazepine Peptidomimetic in Vitro, The Journal of Biological Chemistry, vol. 270, No. 11, pp. 6221-6226 (1995).
Kohl, N.E., et al., "Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice," Nature Medicine, vol. 1, No. 8 (1995).
Bolton, G.L., et al., "Modified Peptide Inhibitors of Ras Farnesyl Protein Transferase," Handout from Poster Session, 209th ACS Meeting, Apr. 2-7, 1995.
Bolton, G.L., et al., "The SAR of Tripeptide Inhibitors of Ras Farnesyl Protein Transferase," Handout from Poster Session, 209th ACS Meeting, Apr. 2-7, 1995.
Sepp-Lorenzino, L., et al., "A Peptidomimetic Inhibitor of Farnesyl:Protein Transferase Blocks the Anchorage-dependent and-independent Growth of Human Tumor Cell Lines," Cancer Research, vol. 55, pp. 5302-5309 (1995).
Anthony Neville J.
Bergman Jeffrey M.
Dinsmore Chrisopher J.
Gomez Robert P.
MacTough Suzanne C.
Dahlen Garth M.
Daniel Mark R.
Ivy C. Warren
Merck & Co. , Inc.
Muthard David A.
LandOfFree
Inhibitors of farnesyl-protein transferase does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Inhibitors of farnesyl-protein transferase, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Inhibitors of farnesyl-protein transferase will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1960605