Inhibitors of HIV-1 proteinase containing 2-heterosubstituted 4-amino-3-hydroxy-5-phenylpentanoic acid: synthesis, enzyme inhibition, and antiviral activity.

D Scholz, A Billich, B Charpiot, P Ettmayer, P Lehr, B Rosenwirth, E Schreiner, H Gstach

Index: J. Med. Chem. 37 , 3079, (1994)

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Abstract

A convenient procedure for the synthesis of 2-heterosubstituted statine derivatives as novel building blocks in HIV-protease inhibitors has been developed. The synthesis starts with protected L-phenylalaninols, which were converted to gamma-amino alpha, beta-unsaturated esters in a one-pot procedure. A highly diastereoselective epoxidation of the N-protected (E)-enoates, followed by regioselective ring opening of the corresponding 2,3-epoxy esters with a variety of heteronucleophiles, resulted in 2-heterosubstituted statine derivatives. The overall stereo-chemical outcome of the transformations meets the required configuration of HIV-protease inhibitors. The short, synthetically flexible, and highly diastereoselective synthesis of 2-heterosubstituted statines has enabled a broad derivation, covering the S3, S2, and S1'-S3' sites of the enzyme. In a series of 46 derivatives, several potent inhibitors were obtained with Ki values as low as 3.4 nM and antiviral activity in the lower nanomolar-range. The structural parameters of the compounds which determine the potency of inhibition and selectivity for the viral enzyme are discussed.