Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-11-24
1996-12-17
Springer, David B.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514464, 549475, 549448, 546169, C07D40712, C07D30720, A61K 3134
Patent
active
055853978
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a novel class of sulfonamides which are aspartyl protease inhibitors. In one embodiment, this invention relates to a novel class of HIV aspartyl protease inhibitors characterized by specific structural and physicochemical features. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting HIV-1 and HIV-2 protease activity and consequently, may be advantageously used as anti-viral agents against the HIV-1 and HIV-2 viruses. This invention also relates to methods for inhibiting the activity of HIV aspartyl protease using the compounds of this invention and methods for screening compounds for anti-HIV activity.
BACKGROUND OF THE INVENTION
The human immunodeficiency virus ("HIV") is the causative agent for acquired immunodeficiency syndrome ("AIDS")--a disease characterized by the destruction of the immune system, particularly of CD4.sup.+ T-cells, with attendant susceptibility to opportunistic infections--and its precursor AIDS-related complex ("ARC")--a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss.
As in the case of several other retroviruses, HIV encodes the production of a protease which carries out post-translational cleavage of precursor polypeptides in a process necessary for the formation of infectious virions (S. Crawford et al., "A Deletion Mutation in the 5' Part of the pol Gene of Moloney Murine Leukemia Virus Blocks Proteolytic Processing of the gag and pol Polyproteins", J., Virol., 53, p. 899 (1985)). These gene products include pol, which encodes the virion RNA-dependent DNA polymerase (reverse transcriptase), an endonuclease, HIV-protease, and gag, which encodes the core-proteins of the virion (H. Toh et al., "Close Structural Resemblance Between Putative Polymerase of a Drosophila Transposable Genetic Element 17.6 and pol gene product of Moloney Murine Leukemia Virus", EMBO J. 4, p. 1267 (1985); L. H. Pearl et al., "A Structural Model for the Retroviral Proteases", Nature, pp. 329-351 (1987); M. D. Power et al., "Nucleotide Sequence of SRV-1, a Type D Simian Acquired Immune Deficiency Syndrome Retrovirus", Science, 231, p. 1567 (1986)).
A number of synthetic anti-viral agents have been designed to target various stages in the replication cycle of HIV. These agents include compounds which block viral binding to CD4.sup.+ T-lymphocytes (for example, soluble CD4), and compounds which interfere with viral replication by inhibiting viral reverse transcriptase (for example, didanosine and zidovudine (AZT)) and inhibit integration of viral DNA into cellular DNA (M. S. Hirsh and R. T. D'Aqulia, "Therapy for Human Immunodeficiency Virus Infection", N. Eng. J. Med., 328, p. 1686 (1393)). However, such agents, which are directed primarily to early stages of viral replication, do not prevent the production of infectious virions in chronically infected cells. Furthermore, administration of some of these agents in effective amounts has led to cell-toxicity and unwanted side effects, such as anemia and bone marrow suppression.
More recently, the focus of anti-viral drug design has been to create compounds which inhibit the formation of infectious virions by interfering with the processing of viral polyprotein precursors. Processing of these precursor proteins requires the action of virus-encoded proteases which are essential for replication (Kohl, N. E. et al. "Active HIV Protease is Required for Viral Infectivity" Proc, Natl. Acad. Sci. USA, 85, p. 4686 (1988)). The anti-viral potential of HIV protease inhibition has been demonstrated using peptidal inhibitors. Such peptidal compounds, however, are typically large and complex molecules that tend to exhibit poor bioavailability and are not generally consistent with oral administration. Accordingly, the need still exists for compounds that can effectively inhibit the action of viral proteases, fo
REFERENCES:
patent: 4330542 (1992-05-01), Descamps et al.
patent: 5196438 (1993-03-01), Martin et al.
patent: 5354866 (1994-10-01), Kempf et al.
G. Fontenot et al., "PCR Amplification of HIV-1 Proteinase Sequences Directly from Lab Isolates Allows Determination of Five Conserved Domains", Virology, 190, pp. 1-10 (1992).
A. Goldblum, "Modulation of the Affinity of Aspartic Proteases by the Mutated Residues in Active Site Models", FEBS, 261, pp. 241-244 (1990).
J. R. Huff, "HIV Protease: A Novel Chemotherapeutic Target for AIDS", Journal of Medicinal Chemistry, 34(8), pp. 2305-2314 (1991).
K. Y. Hui et al., "A Rational Approach in the Search for Potent Inhibitors Against HIV Proteinase", FASEB, 5, pp. 2606-2610 (1991).
X. Lin et al., "Enzymic Activities of Two-Chain Pepsinogen, Two-Chain Pepsin, and the Amino-Terminal Lobe of Pepsinogen", J. Biol. Chem., 267(24), pp. 17257-17263 (1992).
K. P. Manfredi et al., "Examination of HIV-1 Protease Secondary Structure Specificity Using Conformationally Constrained Inhibitors", J. Med. Chem., 34, pp. 3395-3399 (1991).
J. A. Martin, "Recent Advances in the Design of HIV Proteinase Inhibitors", Antiviral Research, 17, pp. 265-278 (1992).
M. Miller et al., "Crystal Structure of a Retroviral Protease Proves Relationship to Aspartic Protease Family", Nature, 337, pp. 576-579 (1989).
J. Palca, "Shooting at a New HIV Target", Science, 247, p. 410 (1990).
N. A. Roberts, "Rational Design of Peptide-Based HIV Proteinase Inhibitors", Science, 248, pp. 358-361 (1990).
S. Scharpe et al., "Proteased and Their Inhibitors: Today and Tomorrow", Biochimie, 73, pp. 121-126 (1991).
S. K. Sharma et al., "Could Angiotensin I Be Produced from a Renin Substrate by the HIV-1 Protease?", Anal. Biochem.,198, pp. 363-367 (1991).
Bhisetti Govinda R.
Murcko Mark A.
Tung Roger D.
Haley, Jr. James F.
Hsi Jeffrey D.
Springer David B.
Vertex Pharmaceuticals Incorporated
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