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
National Institutes of Health NIH • US Department of Health and Human Services
Publication Number
US-9676771-B2
Publication Date
2017-06-13
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 methods and compositions for inhibiting drug-resistant HIV-1 integrase in a subject by administering therapeutically effective amounts of compounds of formula I, as well as related formula IV, V, and VI compounds, or their pharmaceutically acceptable salts or esters. These compounds are characterized by specific substitutions and structures delineated in the patent, including variations in halogenation, substitution at various positions, and functional groups such as hydroxy, amino, and sulfonyl moieties.
The problem being addressed is the low to moderate genetic barrier to resistance and extensive cross-resistance exhibited by currently FDA-approved HIV integrase inhibitors like raltegravir and elvitegravir. This cross-resistance creates a critical need for novel inhibitors that exhibit improved efficacy against raltegravir-resistant strains of HIV-1 integrase. The disclosed compounds specifically aim to overcome resistance to raltegravir and evitegravir medications, thereby providing enhanced treatment options for drug-resistant HIV infections.
Claims Coverage
The patent includes multiple independent claims covering methods of treatment, compound compositions, and their specific structural features. There are four independent claims identified that focus on methods of inhibiting drug-resistant HIV-1 integrase using compounds of various formulae and the compounds themselves with defined substituents.
Method of inhibiting drug-resistant HIV-1 integrase with compounds of formula I
Administering a therapeutically effective amount of a compound of formula I, or pharmaceutically acceptable salt or ester thereof, characterized by specific structural features including substituents Z1-Z5 where at least one or two are halogen, and defined groups R4, R5, R6, R7, R8, and R9.
Method of inhibiting drug-resistant HIV-1 integrase with compounds of formula IV
Using compounds of formula IV or pharmaceutically acceptable salts or esters thereof having specified substituents R4, R5, R6, R7 and R8/R9 as defined, wherein R6 may be hydroxyalkyl.
Composition of compound of formula IV having specific substitution
Compounds of formula IV or pharmaceutically acceptable salts or esters with R6 being hydroxyalkyl and R4 being NH2, with detailed substitution variations aimed at overcoming resistance.
Composition of compounds of formulae V and VI interacting with specific integrase amino acids
Compounds of formula VI modified at position R6 to interact with amino acid residues Thr122, Ser119, Gly118, Pro142, Tyr143 within a cavity of HIV-1 integrase to improve binding especially to drug-resistant integrases.
The independent claims collectively encompass methods for treating drug-resistant HIV-1 integrase infections with specified novel compounds and compositions, where the inventive features include defined substitutions particularly targeting resistant integrase strains and unique binding interactions with the enzyme's active site amino acid residues.
Stated Advantages
The compounds exhibit high inhibitory potency against wild-type HIV-1 integrase and against raltegravir- and elvitegravir-resistant HIV-1 integrase.
Certain compounds display therapeutic selectivity indices greater than 10,000 based on low cytotoxicity and nanomolar efficacies.
The novel binding interactions involving specific amino acid residues in HIV-1 integrase provide a new mode of action important for retaining potency against drug-resistant mutants.
Documented Applications
Treating HIV or AIDS by inhibiting drug-resistant HIV-1 integrase in subjects infected with HIV using compounds of formula I, IV, V, or VI.
Preventing HIV infection prophylactically by administering therapeutically effective amounts of the disclosed compounds.
Co-administering these compounds with other anti-HIV or anti-AIDS therapeutic agents, including various classes of HIV inhibitors such as reverse transcriptase and protease inhibitors, fusion inhibitors, and others, as components of combination antiretroviral therapy.
Using these compounds in the manufacture of medicaments for treatment of AIDS or HIV infection.
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