Hydroxyethylamine -based inhibitor

Besides hydroxyethylamine-based inhibitors, 1,2-dihydroxyethylene-based inhibitors were also explored [58]. Only compoimds with the (R,R,R,R)-configuration at the four central carbon atoms demonstrated any inhibitory potency, and a hydroxyindan substituent at the terminal nitrogen atoms improved activity. Hence (2R,3R,4R,5R)-2,5-bis[(prop-2-en-l-yl)oxy]-3,4-dihydroxy-N, N -bis[(lS,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl]hexanediamide was selected for an optimization study ( ipUsmepsini = 163 nM, K =... 

Finally, the integration of combinatorial chemistry with other drug discovery tools is occurring. The identification of hydroxyethylamine-based inhibitors of cathepsin D by Ellman (libraries 1.14a,b and 1.15), and the penultimate derivation of selective MMP-3 inhibitors from a library of N-carboxyalkyl amino acid by researchers at DuPont Merck (library 1.23), represent two illustrations of the successful merger of structure-based ligand design and library synthesis. The recent introduction of S AR by NMR methodology for lead discovery has also been used in conjunction with a combinatorial library (library 4.12). 

Scheme 3 Microwave-assisted synthesis of N-substituted hydroxyethylamine-based plasmepsin inhibitor...

Beaulieu PL, Wemic D (19%) Preparation of Aminoalkyl Chlorohydiin HydrochlOTides Key Building Blocks for Hydroxyethylamine-Based HTV Protease Inhibitors. J Oig Chem 61 3635... 

The strategy of designing saquinavir was based on the transition-state mimetic concept, an approach that has been used successfully in the design of potent inhibitors of renin and other aspartic proteases [10]. From the variety of nonscissile transition-state analogs of a dipeptide, the hydroxyethylamine mimetic was selected because it most readily accommodates the amino acid moiety characteristic of the Phe-Pro and Tyr-Pro cleavage sequence of the... 

Swain AL, Miller M, Green J, Rich DH, Schneider J, Kent, SBH, Wlodawer A. X-ray crystallographic structure of a complex between a synthetic protease of Human Immunodeficiency Virus 1 and a substrate-based hydroxyethylamine inhibitor. Proc. Natl. Acad. Sci. USA. 1990 87 8805-8809. 

Hydroxyethylamine (HEA) BACE-1 inhibitors 2, 2-Dioxo-isothiochromanes Chroman-HEA derivatives Hydroxyethylene-based BACE-1 Inhibitors Iminopyrimidinone derivatives... 

A. L. Swain, M. M. Miller, J. Green, D. H. Rich, J. Schneider, S. B. H. Kent, and A, Wlodawer, Proc. Natl. Acad. Sci., V.S.A., 87, 8805 (1990). X-Ray Crystallographic Struc- ture of a Complex Between a Synthetic Protease of Human Immunodeficiency Virus 1 and a Substrate-Based Hydroxyethylamine Inhibitor. 

The discovery of peptide-based substrate-mimicking HIVPI was directed towards the synthesis of substrate analogs in which the scissile bond was replaced by a non-cleavable isostere with tetrahedral geometry that could mimic the tetrahedral transition-state of the proteolytic reaction. Thus, several inhibitors with hydroxyethylene or hydroxyethylamine isostere replacement were prepared to bind with the enzyme as shown in Fig. 3a [31]. However, the clinical development of peptide-derived compounds was hindered by their poor pharmacokinetics, including low oral bioavailability, rapid excretion and complex (expensive) synthesis [44,45]. Therefore, recently more... 

All the US-FDA approved Pis except Tipranavir (7) are substrate-based peptidic inhibitors. These inhibitors were designed using the "transition state peptidomimetic principle, which means that in the inhibitors the hydrolyzable peptide linkage is replaced by a non-hydrolyzable transition-state isostere (Fig. 11a) [158]. A munber of such isosteres were studied including statin, norstatin, hydroxyethylene, reduced amide, hydroxyethylamine, hydroxyethyl urea, monoalcohol, diol and aminodiols (Fig. 11b) [158]. Various classes of inhibitors containing dihydroxyethylene transition state isosteres were extensively developed. As an alternative to the peptide-based approach penicillin-derived C2 symmetric compounds were also pursued. 

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