HIV inhibitors
Inventors
Debnath, Asim Kumar • Curreli, Francesca • Kwong, Peter D. • Kwon, Young Do
Assignees
New York Blood Center Inc • US Department of Health and Human Services
Publication Number
US-9309237-B2
Publication Date
2016-04-12
Expiration Date
2032-09-06
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Abstract
Chemical compounds that inhibit retroviruses are presented herein. More particularly, this disclosure provides small molecule compounds that inhibit infection with, or treat infection caused by, human immunodeficiency viruses.
Core Innovation
The invention discloses chemical compounds that inhibit retroviruses, specifically small molecule compounds that inhibit infection with, or treat infection caused by, human immunodeficiency viruses (HIV). The disclosure provides pharmaceutical compositions comprising such compounds, including oxalamide, succinamide, and other structural series, and methods for treating HIV infection by administering these compounds.
The problem addressed by the invention arises from the global HIV epidemic where approximately 36 million people are living with HIV-1. While highly active anti-retroviral therapy (HAART) has reduced morbidity and mortality, patients develop drug resistance that severely limits treatment options. Existing therapies' failure reinforces the critical need to develop new classes of anti-HIV-1 drugs targeting novel mechanisms to broaden treatment scope and reduce treatment-resistant HIV-1 variants.
The invention focuses on inhibiting the early stages of HIV infection involving the attachment of HIV glycoprotein gp120 to the host CD4 receptor. This interaction forms a conserved Phe43 cavity on gp120 critical for viral entry. Small molecules that can insert into the Phe43 cavity and interact with residues such as Asp368 can inhibit HIV infection. Prior compounds like NBD-556 bind this cavity but lack interactions with certain residues, limiting potency. The invention provides novel compounds that effectively bind within the Phe43 cavity, including additional interactions at the cavity entrance to yield more potent antivirals.
Claims Coverage
There are two independent claims: one directed to a pharmaceutical composition comprising a compound represented by specified formulas, and the other directed to a method for inhibiting or treating HIV infection by administering such compounds.
Pharmaceutical composition comprising HIV inhibitory compounds
A pharmaceutical composition comprising a compound represented by a formula where Ph1, Rt, Ar1, and Cy1 are defined as optionally substituted phenyl, alkyl, heteroaryl, or heterocyclyl groups, including pharmaceutically acceptable salts or esters thereof.
Method for treating HIV infection using the composition
A method for inhibiting infection with HIV or treating HIV infection comprising administering to a patient a pharmaceutically effective amount of the compound of the disclosed formula or its pharmaceutically acceptable salt or ester, optionally in combination with other therapeutic agents.
The claims cover compositions containing novel small molecule HIV inhibitors with defined structural features effective in inhibiting HIV infection and methods for using these compositions therapeutically.
Stated Advantages
The compounds inhibit HIV infection by targeting a conserved cavity in gp120, blocking virus-host cell interaction.
They have demonstrated broad antiviral activity against laboratory-adapted and primary HIV-1 strains, including drug-resistant variants.
The compositions can be administered via multiple routes and formulated with various excipients and additional therapeutics.
Documented Applications
Treatment and prevention of HIV-1 infection in subjects at risk or infected.
Use in combination therapies with other anti-HIV agents such as reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, integrase inhibitors, and chemokine receptor inhibitors.
Formulation into pharmaceutical compositions suitable for oral, parenteral, inhalative, transdermal, transmucosal, rectal, intravaginal, and other administrations.
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