Farnesyl protein inhibitor

Farnesyl protein inhibitor 2 Flavones 254 Fluorous phases 112 Fluorous Ugi reactions 115 Functional group transformations 25... 

Fig. 1 Heterocycles bearing a 2-pyridone moiety with wide range of medicinal applications. Amrinone WIN 40680 1 is a cardiotonic agent for the treatment of heart failure. ZAR-NESTRA 2 is a selective farnesyl protein inhibitor and NP048 3 is a pilicide with novel antibacterial properties. The 2-pyridones 4, 5 and 6 are schematic representations of the three categories of 2-pyridones that wiU be covered in this chapter i.e., substituted 2-pyridones 4, 2-quinolones 5 and other ring-fused 2-pyridones 6...

Abstract Over a decade has passed since the first report describing farnesyl protein transferase (FTase) and tetrapeptide inhibitors triggered a search for small-molecule inhibitors that could be developed as oral therapeutics. There are now several farnesyl protein inhibitors (FTIs) in various phases of clinical development and at least two compounds have entered phase III. The published data suggest some disappointing activity in the major solid tumors, with more promising activities emerging from studies of hemato-... 

The protein Ras, an important intracellular signal transducer, is crucially involved in the development of tumor growth. The farnesylation of Ras, catalyzed by the enzyme Ras-farnesyl-transferase, is essential to its proper functioning in the normal and in the transformed state. Therefore, the inhibition of Ras lipidation has become a promising target for the development of new classes of anti-tumor agents. This review focuses on the different classes of Ras-farnesyl-transferase inhibitors and compares their biological properties and modes of action in vitro as well as in vivo. 

Although FTase inhibitors influence the farnesylation of Ras they are likely to interfere with the posttranslational modifications of other CAAX-containing proteins as well. Apart from the approximately 20 farnesylated proteins that are known today, farnesylation is also required for normal Ras function which in turn is critical for normal cell viability. For these reasons farnesyltransferase... 

Inhibitors of farnesyl protein transferase 2003BM L4365... 

Kaminski, J.J., Rane, D.F., Snow, M.E., Weber, L, and Rothofsky, M.L Identification of novel farnesyl protein transferase inhibitors using three-dimensional database searching methods./. Med. Chem. 1997, 40, 4103-4112. 

Horvath D. (2001b) ComPharm—Automated comparative analysis of phar-macophoric patterns and derived QSAR approaches, novel tools in high throughput drug discovery. A proof-of-concept study applied to farnesyl protein transferase inhibitor design. In M Diudea (ed), QSPR/QSAR Studies by Molecular Descriptors, pp. 395-439, Nova Science Publishers, New York, USA. 

Keywords Farnesyl transferase inhibitor Protein prenylation Ras protein ... 

Fig. 4 CAAX competitive heterocyclic farnesyl protein transferase inhibitors. The inhibitors shown in the first row are reported to be in phase I, II, or III clinical development...

Fig. 6 Inhibitors of farnesyl protein transferase, which are competitive for farnesyl pyrophosphate binding...

Patnaik A, Rowinsky EK (2001) Early clinical experience with farnesyl protein transferase inhibitors. In Sebti SM, Hamilton AD (eds) Farnesyltransferase inhibitors in cancer therapy. Humana, Totowa, NJ, pp 233-249... 

End DW, Mevellec L, Angibaud P (2007) Farnesyl Protein Transferase Inhibitors Medicinal Chemistry, Molecular Mechanisms, and Progress in the Clinic. 1 115-150... 

Protein farnesyltransferase (PFT) is responsible for farnesylation of cellular proteins, and PFT inhibitors have recently been developed for treatment of diseases involving farnesylated proteins. 

Synthesis of a Selective, Non-Peptide, Non-Sulfhydryl Farnesyl Protein Transfer Inhibitor (Antitumor Agent)... 

Schering Plough demonstrated the kinetic resolution of a secondary amine (24) via enzyme-catalyzed acylation of a pendant piperidine (Scheme 7.13) [32]. The compound 27 is a selective, non-peptide, non-sulfhydryl farnesyl protein transfer inhibitor undergoing clinical trials as a antitumor agent for the treatment of solid tumors. The racemic substrate (24) does not contain a chiral center but exists as a pair of enantiomers due to atropisomerism about the exocylic double bond. The lipase Toyobo LIP-300 (lipoprotein lipase from Ps. aeruginosa) catalyzed the isobu-tylation of the (+) enantiomer (26), with MTBE as solvent and 2,2,2-trifluoroethyl isobutyrate as acyl donor [32]. The acylation of racemic 24 yielded (+) 26 at 97% and (-) 25 at 96.3% after 24h with an E >200. The undesired enantiomer (25)... 

Scheme 7.13 Enzymatic resolution for the synthesis of 27 for the sythesis of selective, non-peptide, non-sulfhydryl farnesyl protein transfer inhibitor currently undergoing phase II clinical trials for the treatment of solid tumors.

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