Trifluoromethyl ketones, elastase inhibitors

This approach has been mainly applied to peptide-based inhibitors of proteases, where the inhibitory molecule is a peptide with a transition state isostere appended to it, and the cognate substrate is simply a peptide of the same amino acid sequence, but lacking the isostere functionality. Examples where good correlations between the free energy of inhibitor binding and the free energy of kcJKM have been found, include peptide-trifluoromethyl ketone inhibitors of human leukocyte elastase (Stein et al., 1987) and peptide-phosphonamidate inhibitors of the metalloprotease ther-molysin (Bartlett and Marlowe, 1983). 

Veale, C. A., Bernstein, R R., Bryant, C., et al. (1995) Nonpeptidic inhibitors of human leukocyte elastase. 5. Design, synthesis, and X-ray crystallography of a series of orally active 5-aminopyrimidin-6-one-containing trifluoromethyl ketones. J. Med. Chem., 38, 98-108. 

S. Feeney, B. C. Gomes, B. J. Kosmider, G. B. Steelman, R. M. Thomas, E. P. Vacek, J. C. Williams, D. J, Wolanin, and S. A. Woolson, ]. Med. Chem., 38, 98 (1995). Non-Peptidic Inhibitors of Human Leukocyte Elastase. 5. Design, Synthesis, and X-Ray Crystallography of a Series of Orally Active 5-Aminopyrimidin-6-one-Containing Trifluoromethyl Ketones. 

Fluoroalkyl P-amino alcohols are precursors of the corresponding fluoroalkyl peptidyl ketones which have been shown to be effective inhibitors of proteolytic enzymes, such as serine proteases/ (chymotrypsin/ elastases/ trypsin/ thrombin/ ) aspartyl proteasesor cysteine proteases, In some cases fluoroalkyl p-amino alcohols are themselves inhibitors of the same enzymes/ " This interest in these fluoroalkyl P-amino alcohols 1 aroused efforts for stereoselective and enantioselective synthetic methodsA number of approaches have been reported during these last years, either through the addition of trifluoromethyl equivalent anion to protected aldehyde or through the building block approach. However the main problem of all these approaches is the diastereoselectivity. 

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