Benzamide-containing inhibitors of farnesyl-protein transferase

Details Benzamide-containing inhibitors of farnesyl-protein transferase Benzamide-containing inhibitors of farnesyl-protein transferase

1995-03-29

1996-11-26

Higel, Floyd D.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514399, 514562, 5483127, 5483381, 562428, C07D27704, C07D27712, C07C23720, C07C32329, C07C32110

Patent

active

055786294

ABSTRACT:
The present invention comprises peptidomimetic compounds which comprise a suitably substituted aminoalkylbenzamide moiety. The instant compounds inhibit the farnesyl protein transferase enzyme and the farnesylation of certain proteins. Furthermore, the instant farnesyl protein transferase inhibitors 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: 5179117 (1993-01-01), Maduskuie
patent: 5238922 (1993-08-01), Graham et al.
patent: 5256645 (1993-10-01), Branca 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.
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 SZA-S8 Interrupts the MAP Kinase Activation Pathway in H-Res-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).
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., "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).
Nlgam, M., et al., "Potent Inhibition of Human Tumor p21 ras Farnesyltransferase by A1A2-lacking p21 ras CA1A2X Peptidomimetics", The Journal of Biol. Chem., vol. 268, Issue of Oct. 5, pp. 20695-20698 (1993).
Pompliano, D. L., "Steady-State Kinetic Mechanism of Ras Farnesyl:Protein Transferase", Biochemistry, vol. 31, pp. 3800-3807 (1992).
Qian, T., et al., "Design and Structural Requirements of Potent Peptidomimetic Inhibitors of p21 ras Farnesyltransferase", The Journal of Biol. Chem., vol. 269, No. 17, Issue of Apr. 29, pp. 12410-12413 (1994).
Vogt, A., et al., "A Non-peptide Mimetic of Ras-CAAX: Selective Inhibition of Farnesyltransferase and Ras Processing", The Journal of Biol. Chem., vol. 270, No. 2, Issue of Jan. 13, pp. 660-664 (1995).

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