Inhibitors of farnesyl-protein transferase

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Patent

Rate now

  [ 0.00 ] – not rated yet Voters 0   Comments 0

Details

5483147, C07D40302, A61K 31415, A61K 3140

Patent

active

059729848

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: 3399193 (1968-08-01), Giraldi et al.
patent: 3737422 (1973-06-01), Fluoret
patent: 3996366 (1976-12-01), Baker et al.
patent: 4241060 (1980-12-01), Smithen
patent: 4324792 (1982-04-01), Bradshaw et al.
patent: 4472305 (1984-09-01), Hansen et al.
patent: 4591648 (1986-05-01), Jones et al.
patent: 5019572 (1991-05-01), Claremon et al.
patent: 5043268 (1991-08-01), Stock
patent: 5071837 (1991-12-01), Doherty et al.
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: 5401851 (1995-03-01), Boyd et al.
patent: 5420245 (1995-05-01), Brown et al.
patent: 5439918 (1995-08-01), de Solms et al.
patent: 5478934 (1995-12-01), Yuan et al.
patent: 5504212 (1996-04-01), de Solms et al.
patent: 5534537 (1996-07-01), Ciccarone et al.
patent: 5686472 (1997-11-01), Anthony et al.
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, pp. 792-797 (1995).
Arrang, J.-M., et al., "Highly potent and selective ligands for histamine H3-receptors," Nature, vol. 327, No. 6118, pp. 117-123 (1987).
Giraldi, P.N., et al., Arzneimettel-Forschu NG Drug Res., vol. 20, No. 1, pp. 52-55 (1970).
Shafiee, A., et al., "Nitroimidazoles VIII [1.] Syntheses, Antibacterial and Antifungal Activities of 2-Pyridyl-Nitroimidazoles," J. Sci., I.R. Iran, vol. 1, No. 3, pp. 197-201 (1990).
Giraldi, P.N., et al., "Studies on Antiprotozoans. Synthesis and Biological Activity of Some Styrylimidazole Derivatives," J. Med. Chem., vol. 11, No. 1, pp. 66-70 (1967).
Kukkola, Paivi J. et al., "Optimization of Retro-Thiorphan for Inhibition of Endothelin Converting Enzyme," Biorg. Med. Chem. Lett., vol. 6, No. 6, pp. 619-624 (1996).
Brown, T., et al., "Protection of Histidine Side-chains with n-Benzyloxymethyl-or n-Bromobenzyloxymethyl-groups," J. Chem. Soc. Chem. Commun., vol. 13, pp. 648-649 (1981).
Prior, K. J., et al., Synthesis, vol. 25, No. 3, pp. 247-255 (1988).
Colombo, R., et al., "Acid-labile Histidine Side-chain Protection: the N(n)-t-Butoxymethyl Group," Acid-Labile, vol. 5, pp. 292-293 (1984).
Patel, D. V., et al., "Retro Inverso Tripeptide Renin Inhibitors," Bioorganic and Medicinal Chemistry Letters, vol. 2, No. 9, pp. 1089-1092 (1992).
Colombo, R., et al., Pept. Proc. Eur. Pept. Symp, 17th, pp. 251-256 (1983).
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).
Krontiris, T.G., "Molecular and Cellular Biology of Cancer," Int. Med., 4th ed., pp. 699-715 (1995).

LandOfFree

Say what you really think

Search LandOfFree.com for the USA inventors and patents. Rate them and share your experience with other people.

Rating

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.

Rate now

     

Profile ID: LFUS-PAI-O-765117

  Search
All data on this website is collected from public sources. Our data reflects the most accurate information available at the time of publication.