POTENT HIV PROTEASE INHIBITORS - THE DEVELOPMENT OF TETRAHYDROFURANYLGLYCINES AS NOVEL P(2)-LIGANDS AND PYRAZINE AMIDES AS P(3)-LIGANDS

A series of protease inhibitors bearing constrained unnatural amino acids at the P2-position and novel heterocycles at the P3-position of compound 1 (Ro 31-8959) were synthesized, and their in vitro enzyme inhibitory and antiviral activities were evaluated. Replacement of P2-asparagine of compound 1 with (2S,3'R)-tetrahydrofuranylglycine resulted in improvement in enzyme inhibitory as well as antiviral potencies (compound 23). Interestingly, incorporation of (2S,3'S)-tetrahydrofuranylglycine at the P2-position proved to be less effective. The resulting compound 24 was 100-fold less potent than the 2S,3R-isomer (compound 23). This stereochemical preference indicated a hydrogen-bonding interaction between the tetrahydrofuranyl oxygen and the residues of the S2-region of the enzyme active site. Furthermore, replacement of P3-quinolinoyl ligand of 1 with various novel heterocycles resulted in potent inhibitors of HIV proteases. Of particular interest, compound 2 with (2S,3'R)-tetrahydrofuranylglycine at P2 and pyrazine derivative at P3 is one of the most potent inhibitors of HIV-1 (IC50 value 0.07 nM) and HIV-2 (IC50 value 0.18 nM) proteases. Another important result in this series is the identification of compound 27 in which the P2-P3-amide carbonyl has been removed. The resulting compound 27 has exhibited improvement in antiviral potency while retaining the enzyme inhibitory potency similar to compound 1.
Publisher
AMER CHEMICAL SOC
Issue Date
1993-08
Language
ENG
Keywords

IMMUNODEFICIENCY VIRUS PROTEASE; ALPHA-AMINO-ACIDS; DRUG DESIGN; FACILE; TARGET; AIDS

Citation

JOURNAL OF MEDICINAL CHEMISTRY, v.36, no.16, pp.2300 - 2310

ISSN
0022-2623
DOI
10.1021/jm00068a006
URI
http://hdl.handle.net/10203/65911
Appears in Collection
CH-Journal Papers(저널논문)
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