Abstract
Replication of the human immunodeficiency virus (HIV) is dependent upon the enzyme HIV integrase (IN), one of three essential enzymes encoded in the viral genome. HIV-1 IN catalyzes the insertion of the proviral DNA into the host genome (strand transfer). HIV-1 IN therefore presents an attractive chemotherapeutic target for the treatment of HIV infection and AIDS that could provide patients and physicians with an additional option for treatment. Assays were developed to identify inhibitors of IN strand transfer. Diketoacid lead compounds were explored and developed into a variety of heterocyclic templates that are potent inhibitors of integrase strand transfer with suitable medicinal chemical properties for treating HIV infection and AIDS. The 1,6-naphthyridine L-870810 (Antiviral activity in cells IC95 NHS = 102 nM, n=237), was shown to be efficacious in reducing viral RNA by 1.7 log units after doses of 400mg BID to HIV infected patients. Optimization of physical properties led to L-900564, an inhibitor of HIV IN that has excellent cell potency in the presence of protein (Antiviral activity in cells IC95 NHS = 16 nM, n=15), excellent activity against mutants raised to HIV integrase inhibitors, and a very good pharmacokinetic profile..
Keywords: HIV, AIDS, integrase, strand transfer, diketoacid, diaryldiketone, 1,6-naphthyridine
Current Topics in Medicinal Chemistry
Title: HIV Integrase Inhibitors: From Diketoacids to Heterocyclic Templates: A History of HIV Integrase Medicinal Chemistry at Merck West Point and Merck Rome (IRBM)
Volume: 7 Issue: 13
Author(s): Melissa S. Egbertson and Melissa S. Egbertson
Affiliation:
Keywords: HIV, AIDS, integrase, strand transfer, diketoacid, diaryldiketone, 1,6-naphthyridine
Abstract: Replication of the human immunodeficiency virus (HIV) is dependent upon the enzyme HIV integrase (IN), one of three essential enzymes encoded in the viral genome. HIV-1 IN catalyzes the insertion of the proviral DNA into the host genome (strand transfer). HIV-1 IN therefore presents an attractive chemotherapeutic target for the treatment of HIV infection and AIDS that could provide patients and physicians with an additional option for treatment. Assays were developed to identify inhibitors of IN strand transfer. Diketoacid lead compounds were explored and developed into a variety of heterocyclic templates that are potent inhibitors of integrase strand transfer with suitable medicinal chemical properties for treating HIV infection and AIDS. The 1,6-naphthyridine L-870810 (Antiviral activity in cells IC95 NHS = 102 nM, n=237), was shown to be efficacious in reducing viral RNA by 1.7 log units after doses of 400mg BID to HIV infected patients. Optimization of physical properties led to L-900564, an inhibitor of HIV IN that has excellent cell potency in the presence of protein (Antiviral activity in cells IC95 NHS = 16 nM, n=15), excellent activity against mutants raised to HIV integrase inhibitors, and a very good pharmacokinetic profile..
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Cite this article as:
Melissa S. Egbertson and Egbertson S. Melissa, HIV Integrase Inhibitors: From Diketoacids to Heterocyclic Templates: A History of HIV Integrase Medicinal Chemistry at Merck West Point and Merck Rome (IRBM), Current Topics in Medicinal Chemistry 2007; 7 (13) . https://dx.doi.org/10.2174/156802607781212248
DOI https://dx.doi.org/10.2174/156802607781212248 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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