Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-06
2004-02-10
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S194000
Reexamination Certificate
active
06689793
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods of using compounds as non-nucleoside inhibitors of reverse transcriptase (RT) that are effective against human immunodeficiency virus (HIV), including mutant strains of HIV, and effective in the treatment of multi-drug resistant HIV infection.
BACKGROUND OF THE INVENTION
Agents currently used to treat HIV infection attempt to block replication of the HIV virus by blocking HIV reverse transcriptase (RT) or by blocking HIV protease. Three categories of anti-retroviral agents in clinical use are nucleoside analogs (such as AZT), protease inhibitors (such as nelfinavir), and the recently introduced non-nucleoside reverse transcriptase inhibitors (NNI), such as nevirapine.
The recent development of potent combination anti-retroviral regimens has significantly improved prognosis for persons with HIV and AIDS. Combination therapies are a significant factor in the dramatic decrease in deaths from AIDS (a decrease in death rate as well as absolute number). The most commonly used combinations include two nucleoside analogs with or without a protease inhibitor.
Nevirapine is currently the only NNI compound, which has been used in combination with AZT and/or protease inhibitors for the treatment of HIV. A new series of effective drug cocktails will most likely involve other NNIs in combination with nucleoside and protease inhibitors as a triple action treatment to combat the growing problem of drug resistance encountered in single drug treatment strategies.
The high replication rate of the virus unfortunately leads to genetic variants (mutants), especially when selective pressure is introduced in the form of drug treatment. These mutants are resistant to the anti-viral agents previously administered to the patient. Switching agents or using combination therapies may decrease or delay resistance, but because viral replication is not completely suppressed in single drug treatment or even with a two-drug combination, drug-resistant viral strains ultimately emerge. Triple drug combinations employing one (or two) nucleoside analogs and two (or one) NNI targeting RT provide a very promising therapy to overcome the drug resistance problem. RT mutant strains resistant to such a triple action drug combination would most likely not be able to function.
Dozens of mutant strains have been characterized as resistant to NNI compounds, including L1001, K103N, V106A, E138K, Y181 C and Y188H. In particular, the Y181 C and K103N mutants may be the most difficult to treat, because they are resistant to most of the known NNI compounds.
Recently, a proposed strategy using a knock-out concentration of NNI demonstrated very promising results. The key idea in this strategy is to administer a high concentration of NNI in the very beginning stages of treatment to reduce the virus to undetectable levels in order to prevent the emergence of drug-resistant strains. The ideal NNI compound for optimal use in this strategy and in a triple action combination must meet three criteria:
1) very low cytotoxicity so it can be applied in high doses;
2) very high potency so it can completely shut down viral replication machinery before the virus has time to develop resistant mutant strains; and
3) robust anti-viral activity against current clinically observed drug resistant mutant strains.
In recent years, structure-based drug design has played an increasingly important role in the development of useful anti-AIDS drugs as seen in the success of HIV protease inhibitor design as disclosed in Deek et al., “HIV-1 Protease Inhibitors”,
J. Acquired Immune Defic. Syndr. Res. Human Retrovirus,
98:145-185 (1997). Rational drug design is most effective when detailed structural information about the protein-inhibitor complex is available, a requirement which can be a limitation for reverse transcriptase.
While qualitative assessments of RT-inhibitor complexes provide helpful information in the absence of crystal structures, a systematic quantitative prediction of inhibitory activity of new compounds based on available structural information remains a challenge as discussed in Kroeger Smith et al., “Molecular Modeling Studies of HIV-1 Reverse Transcriptase Nonnucleoside Inhibitors: Total Energy of Complexation as a Predictor of Drug Placement and Activity”,
Protein Science,
4:2203-2222 (1995).
Further, while qualitative assessments of RT-inhibitor complexes have provided helpful information in the development of non-nucleoside inhibitors (NNIs), NNIs to date fail to provide potent inhibition of RT with minimal cytotoxicity. In addition, NNIs to date fail to effectively inhibit known, drug-resistant strains of HIV.
What is needed in the art is new antiviral drugs, which have the following characteristics: (1) potent inhibition of RT; (2) minimum cytotoxicity; and (3) improved ability to inhibit known, drug-resistant strains of HIV.
SUMMARY OF THE INVENTION
It has been discovered that certain thiourea compounds of the present invention demonstrate improved potent and specific antiviral activity compared to known therapeutic agents. The thiourea compounds of the present invention possess the ability to inhibit replication of RT with minimum cytotoxicity. Further, the thiourea compounds of the present invention possess an improved ability to inhibit known, non-nucleoside resistant and drug-resistant strains of HIV.
In one aspect, the present invention is directed to piperidinylethyl-substituted, phenoxyethyl-substituted, and fluorophenethyl-substituted thiourea compounds, which inhibit non-nucleoside resistant or drug-resistant reverse transcriptase (RT) and which inhibit replication of a retrovirus, such as human immunodeficiency virus-1 (HIV-1).
The present invention is further directed to a method for inhibiting non-nucleoside resistant or drug-resistant reverse transcriptase activity of a retrovirus, such as HIV-1, comprising contacting the retrovirus with a thiourea compound of the present invention. The present invention is also directed to a method for inhibiting replication of a non-nucleoside resistant or drug-resistant retrovirus, such as HIV-1, comprising contacting the retrovirus with a thiourea compound of the present invention. In addition, the present invention is directed to a method for treating a non-nucleoside resistant or drug-resistant retroviral infection in a subject, such as an HIV-1 infection, comprising administering a thiourea compound of the invention to the subject.
These and other features and advantages of the present invention will become apparent after a review of the following detailed description of the disclosed embodiments and the appended claims.
DETAILED DESCRIPTION OF THE INVENTION
It has been discovered unexpectedly that certain substituted thiourea compounds possess increased activity against non-nucleoside resistant or drug-resistant HIV while maintaining low levels of cytotoxicity. As such, these compounds are particularly useful as active agents for antiviral compositions and for methods of treating viral infections such as HIV infections. Further, the compounds exhibit improved inhibition of multi-drug resistant strains of HIV.
Definitions:
All scientific and technical terms used in this application have meanings commonly used in the art unless otherwise specified. As used in this application, the following words or phrases have the meanings specified.
As used herein, a “retrovirus” includes any virus that expresses reverse transcriptase. Examples of a retrovirus include, but are not limited to, HIV-1, HIV-2, HTLV-I, HTLV-II, FeLV, FIV, SIV, AMV, MMTV, and MoMuLV.
As used herein, “reverse transcriptase (RT)” refers to an enzyme having activity to effect reverse transcription of retroviral RNA to proviral DNA. One means by which RT activity can be determined is by measuring viral replication. One measure of viral replication is the p24 assay described herein.
As used herein, a compound that “inhibits replication of human immunodeficiency virus (HIV)” means a compound that, when contacted with HIV-1, for example, via HIV-infected ce
Uckun Fatih M.
Venkatachalam Taracad K.
Chang Ceila
Merchant & Gould P.C.
Parker Hughes Institute
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