HIV protease inhibitors

Details HIV protease inhibitors HIV protease inhibitors

1997-09-09

2000-03-28

Owens, Amelia

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

C07D24500

Patent

active

060433574

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

This invention relates to HIV protease inhibitors.


BACKGROUND OF THE INVENTION

In recent years, the worldwide research focus on the development of anti-HIV drugs has tested the viability of receptor-based drug design and has helped to focus on de novo drug design. The proteinase of the Human Immunodeficiency Virus, HIV-1 protease (Blundell et al., 1990, TIBS 15 425-430; Huff, J., 1991, J. Med. Chem. 34 2305-2314; Darke, P. L. and Huff, J. R., 1994, Adv. Pharm. 25 399-454; Debouck, C., 1992, AIDS Res. & Hum. Retrovir 8 153-164), is a conspicuous example of a receptor for which drug design methodologies have been applied with some success. The rational design of clinically effective inhibitors for this enzyme has remained elusive.
The Human Immunodeficiency Virus (HIV) now infects over 15 million people worldwide, including some 20,000 individuals in Australia. Drugs aimed at treating HIV infection are being rationally developed to target key regulatory proteins that are essential for the replication of HIV. One of these proteins, HIV-1 protease (HIVPR), is an aspartic protease (James, M. N. G. & Sielecki, A. R., 1989, in Biological Macromolecules & Assemblies (Jurnak, F. A. & McPherson, A. M., eds), Wiley, N.Y., Vol. 3, p. 413; Fitzgerald, P. M. & Springer, J. P., 1991, Ann. Rev. Biophys. Chem. 20 299-320) that acts late in the viral replicative cycle by processing polypeptides (Pr160 and Pr50) transcribed from the gag and pol genes. The protease is essential for assembly and maturation of infectious virions but becomes inactivated by a single mutation (Asp25) in the active site, resulting in immature, non-infective virus particles (Kohl et al., supra; Ashorn et al., Proc. Natl. Acad. Sci. U.S.A. 87 7472-7476; Lambert et al., 1992, Antimicrob. Agents. Chemother. 36 982-988). Since inhibitor binding to HIVPR can also prevent infection of immune cells by HIV, the protease is a valid target for chemotherapeutic intervention (Kohl, N. E., 1988, Proc. Natl. Acad. Sci. USA 85 4686-4690; Ashorn et al., supra; Lambert et al., supra). Inhibitors of HIVPR can be expected to be possible treatments for HIV-infections. Indications are that resistance is more difficult to develop against HIVPR inhibitors (Roberts et al., 1990, Science 248 358-631; Craig et al., 1991, Antiviral Res. 16 295-305; Muirhead et al., 1993, 9th Intl. Cong. AIDS (Berlin), Abs PO-B30-2199; Muirhead et al., 1992, Br. J. Clin. Pharm. 34 170-171; Roberts et al., 1992, Biochem. Soc. Trans. 20 513-516) than reverse transcriptase inhibitors (Tomasselli et al., 1992, Chimicaoggi 6-27), but resistance is still proving to be a major problem.
HIVPR is a homo-dimer, consisting of two identically folded 99 amino acid subunits that form a hydrophobic active site cavity. The C.sub.2 symmetry of the enzyme is a unique feature among aspartic proteinases. HIVPR is also characterised by two conformationally flexible flaps (one per subunit) which are able to close around the substrate. The three dimensional crystal structures of both recombinant and synthetic HIVPR have been reported for the enzyme as well as enzyme-inhibitor complexes (Tozser et al., 1992, Biochemistry 31 4793-4800; Swain et al., 1990, Proc. Natl. Acad. Sci. USA 87 8805-8809). The major difference between these enzyme conformations is in the location of the flaps and some residues in the hinge region. The amino acids of HIVPR that line the substrate-binding groove, which is 24 .ANG. long by 6-8 .ANG. diameter, are symmetrically disposed around the catalytic residues located near the centre of the active site.
The first approaches to developing inhibitors of HIVPR involved a combination of analogue-based and mechanism-based drug design that focused on the amino acid sequence of substrates for HIVPR. These inhibitors were based on the observed preference for proteolysis of substrates with a scissile hydrophobic-hydrophobic or aromatic-proline peptide bond (Griffiths, J. T., 1992, Biochemistry 31 5193-5200) and were both potent and selective for HIVPR. Aside from optimising

REFERENCES:
Swain, et al. "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., 87:8805-8809 (1990).
Abbenante, et al. "Regioselective Structural and Functional Mimicry of Peptides. Design of Hydrolytically-Stable Cyclic Peptidomimetic Inhibitors of HIV-1 Protease", J. Am. Chem. Soc., 117:10220-10226 (1995).

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