Methylene ether isosteres

The introduction of the methylene ether isostere t t[CH20] has not been fully exploited (Fig. 7.22) [144, 145]. Several methods have been suggested for the preparation of these peptidomimetics. The methylene ether bond can be obtained by substitution reac- 

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Scheme 7.10. Synthetic routes to the introduction of methylene ether isostere /[CH20] [145],...

The cellular effects of FTase inhibition with 3 were observed with concentrations 5000-50,000 higher than the in vitro IC50 for FTase inhibition by carboxylic acid Id. Incomplete hydrolysis of the lactone in vivo could be partially responsible for this discrepancy in activity. However, it was also found that the lactone prodrug used in the context of the doubly reduced peptide isostere, i.e. 3, was chemically unstable at physiological pH. Rapid cyclization to the diketopiperazine 5 significantly reduced FTase inhibitory activity.40 Simple N-alkylation of the reactive secondary amine to give 4 led to loss of activity vs. FTase. To simultaneously protect the compound from both metabolic inactivation (via peptidases) and chemical instability, isosteric replacements of the second amide bond other than methylene-amino were explored. Since the second amide bond in the tetrapeptide inhibitors could be reduced without loss of activity in vitro, peptide bond replacements which were both rigid (olefin) and flexible (alkyl, ether) were synthesized. 

As seen in Scheme 14, molecular elimination processes (including cage disproportionation reactions) account for about half of the primary decomposition. This is in contrast to the behavior of the Isosteric ethers such as diethyl (177) and methyl n-propyl ethers (88), where these processes are rather less important (Schemes 6 and 7). It is not known whether the formaldehyde formed in reaction 4 (Scheme 14) incorporates the carbon atom from methylene or methyl. 

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