title: Inhibitors of HIV-1 proteinase containing 2-heterosubstituted 4-amino-3-hydroxy-5-phenylpentanoic acid: synthesis, enzyme inhibition, and antiviral activity.
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.
authors.affiliation: Department of Antiretroviral Therapy, SANDOZ Forschungsinstitut Ges.m.b.H., Vienna, Austria.
authors.forename: D
authors.initials: D
authors.lastname: Scholz
authors.forename: A
authors.initials: A
authors.lastname: Billich
authors.forename: B
authors.initials: B
authors.lastname: Charpiot
authors.forename: P
authors.initials: P
authors.lastname: Ettmayer
authors.forename: P
authors.initials: P
authors.lastname: Lehr
authors.forename: B
authors.initials: B
authors.lastname: Rosenwirth
authors.forename: E
authors.initials: E
authors.lastname: Schreiner
authors.forename: H
authors.initials: H
authors.lastname: Gstach
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001665:Binding Sites; D002384:Catalysis; D002478:Cells, Cultured; D015658:HIV Infections / Q000188:drug therapy / Q000201:enzymology; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D015498:HIV-2 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D010421:Pentanoic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D010421:Pentanoic Acids