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amino acids like aminobenzoic acid derivatives (e.g. FTI-276). L-739750 and FTI-276 were normally employed as ester prodrugs (L-744832 and FTI-277, respectively) in order to enhance their absorption (Fig. 9.29). Despite the encouraging in vivo data obtained for these peptidomimetics, there were reservations regarding their clinical use because of their potential thiol-related toxicity; nevertheless, L-744832 has reached clinical trials.108 A combination of the modifications used for the design of L-739750 and FTI-276, with the additional modifications of the replacement of the reduced cysteine moiety by a mercaptoproline and having both the thiol and the carboxylic groups masked as esters, has led to the design of the double pro-drug AZD-3409, which has reached clinical trials.

The main FTase inhibitors under clinical development109 are non-peptidic, heterocyclic compounds such as BMS-214662, tipifarnib (R-115777), L-778123, lonafarnib (SCH-66336), and SCH-226374 that have normally been discovered through screening approaches. BMS-214662, tifiparnib (initially developed as an antifungal agent) and L-778123 contain imidazole rings that are able to coordinate the catalytic zinc cation competing with the cysteine unit at the CAAX motif in Ras. Lonafarnib was discovered through library screening and it does not have a group able to act as a zinc ligand, which led to the design of its imidazole-bearing analogue SCH-226374.

Both tipifarnib and lonafarnib are orally bioavailable, while BMS-24662 and L-7781123 have been studied as intravenous formulations. BMS-24662, tipifarnib110,111 L-778123,112 and lonafarnib113 are under clinical studies against a variety of cancers.

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