Compounds for inhibiting drug-resistant strains of HIV-1 integrase
Inventors
Zhao, Xue Zhi • Smith, Steven • Metifiot, Mathieu • Johnson, Barry • Marchand, Christophe • Hughes, Stephen H. • Pommier, Yves • Burke, Jr., Terrence R.
Assignees
US Department of Health and Human Services
Publication Number
US-10208035-B2
Publication Date
2019-02-19
Expiration Date
2034-05-13
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Abstract
A method of inhibiting drug-resistant HIV-1 integrase in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or ester thereof, having a structure of: wherein X is N, C(OH), or CH; Y is H or OH; each of Z1-Z5 is independently H or halogen; R4 is H, OH, NH2, NHR8, NR8R9 or R8; R5, R6, and R7 is each independently H, halogen, OR8, R8, NHR8, NR8R9, CO2R8, CONR8R9, SO2NR8R9, or R5 and R6 together with the carbon atoms to which R5 and R6 are attached form an optionally-substituted carbocycle or optionally-substituted heterocycle; and R8 and R9 is each independently H, optionally-substituted alkyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted cycloalkylene, optionally-substituted heterocycle, optionally-substituted amide, optionally-substituted ester, or R8 and R9 together with the nitrogen to which R8 and R9 are attached form an optionally-substituted heterocycle.
Core Innovation
The invention discloses a method of inhibiting drug-resistant HIV-1 integrase in a subject by administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or ester thereof. These compounds are structurally defined with specific substituents including variations in X, Y, Z1-Z5, R4, R5, R6, R7, R8, and R9. The compounds include various formulae (I, II, III, IV, V, VI) with defined chemical structures and substituents tailored to inhibit HIV-1 integrase, including drug-resistant strains.
The problem addressed by the invention is that existing FDA-approved HIV integrase inhibitors, raltegravir and elvitegravir, demonstrate a low to moderate genetic barrier to resistance and exhibit extensive cross-resistance. This creates a critical need for inhibitors with improved efficacy against drug-resistant and specifically raltegravir-resistant HIV-1 integrase strains.
The disclosed compounds interact with specific amino acid residues (Thr122, Ser119, Gly118, Pro142, Tyr143) in a cavity of HIV-1 integrase, revealing a new binding pattern that is important in retaining potency against raltegravir-resistant integrase mutants. The compounds exhibit high inhibitory potency against wild-type and drug-resistant HIV-1 integrase with low cytotoxicity and high therapeutic selectivity indices. Methods of using these compounds to inhibit HIV-1 integrase integration, treat HIV infection, prevent HIV infection, and overcome resistance to existing therapies are also disclosed.
Claims Coverage
The patent includes multiple independent claims covering methods of inhibition of drug-resistant HIV-1 integrase and specific compounds defined by chemical formulas with particular substituents. These claims center on inventive features related to chemical structure, resistance profile, and methods of treatment.
Method of inhibiting drug-resistant HIV-1 integrase with specific compounds
A method of inhibiting drug-resistant HIV-1 integrase in a subject by administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or ester thereof, with defined substituents and chemical structure.
Compounds of formula IV with defined substituents
Compounds of formula IV, or pharmaceutically acceptable salt or ester thereof, characterized by specific substituents R4, R5, R6, R7, R8, and R9 that confer inhibitory activity against HIV-1 integrase.
Compounds with halogen substituents enhancing activity
Compounds of formula I or III having at least one of Z1–Z5 as halogen, with R4 as NH2 or other specified amine substitutions improving inhibition potency.
Compounds with R6 substituents targeting integrase amino acid residues
Compounds where R6 is a substituent that interacts with amino acid residues Thr122, Ser119, Gly118, Pro142, Tyr143 in the HIV-1 integrase cavity, enhancing binding and potency against resistant enzyme forms.
Co-administration with other anti-HIV therapeutic agents
The method further includes co-administering the compounds with at least one other anti-HIV therapeutic agent to treat or prevent HIV infection.
The claims cover methods of treating drug-resistant HIV-1 integrase infections using novel compounds with specific chemical structures and substitutions that target key integrase residues, including compounds effective against raltegravir-resistant strains, and the methods include co-administration with other antiretroviral agents.
Stated Advantages
The compounds exhibit high inhibitory potency against both wild-type and drug-resistant HIV-1 integrase.
They demonstrate low cytotoxicity resulting in high therapeutic selectivity indices, sometimes exceeding 10,000.
The new binding pattern of these compounds overcomes resistance to existing FDA-approved integrase inhibitors, especially raltegravir.
Certain compounds have nanomolar efficacy and retain potency against raltegravir-resistant integrase mutants.
Documented Applications
Treatment of AIDS or HIV infection, including in subjects infected with drug-resistant HIV-1 integrase.
Prevention of HIV infection in subjects at risk.
Inhibition of raltegravir-resistant HIV-1 integrase to overcome resistance to current FDA-approved integrase inhibitors.
Use in combination antiretroviral therapy by co-administration with other anti-HIV agents.
Use in pharmaceutical compositions for administration via various routes to subjects in need.
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