Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-03-26
1999-02-16
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514330, 546210, 546226, A61K 31445, C07D21132, C07D21160, C07D40106
Patent
active
058721355
ABSTRACT:
The present invention comprises analogs of the CAAX motif of the protein Ras that is modified by farnesylation in vivo. These CAAX analogs inhibit farnesyl-protein transferase. Furthermore, these CAAX analogues differ from those 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: 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), Desolms et al.
patent: 5340828 (1994-08-01), Graham et al.
patent: 5352705 (1994-10-01), Deana
patent: 5420245 (1995-05-01), Brown et al.
patent: 5504212 (1996-04-01), Desolms et al.
patent: 5686472 (1997-11-01), Anthony et al.
Gibbs, J.B. et al., "Selective Inhibition of Farnesyl-Protein Transferase Blocks Ras Procesing 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 BZA-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. 269, 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).
James, G., et al., Polylysine and CVIM Sequences of K-RasB Dictate Specificity of Prenylation and Confer Resistance to Benzodiaepine Peptidomimetic in Vitro, The Journal of Biological Chemistry, vol. 270, No. 11, pp. 6221-6226 (1995).
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 farneyltransferase inhibitors block the growth of ras-dependent tumors in nude mice", Proc. Natl. Acad. Sci. USA, Med. Sciences, vol. 91, pp. 9141-9145 (1994).
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, pp. 792-797 (1995).
Lorenzino, L.S., et al., "A Peptimomimetic Inhibtor of Farnesyl:Protein Transferase Blocks the Anchorage-dependent and independent Growth of Human Tumor Cell Lines," Cancer Research, 55, pp. 5302-5309 (1995).
Pompliano, D.L., "Steady-State Kinetic Mechanism of Ras Farnesyl:Protein Transferase," Biochemistry, vol. 31, pp. 3800-3807 (1992).
Daniel Mark R.
Merk & Co., Inc.
Muthard David A.
Pecoraro Dianne
Raymond Richard L.
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