Human immunodeficiency virus type-1 (HIV-1) integrase is one of the three virally encoded enzymes required for replication and therefore a rational target for chemotherapeutic intervention in the ...treatment of HIV-1 infection. We report here the discovery of Raltegravir, the first HIV-integrase inhibitor approved by FDA for the treatment of HIV infection. It derives from the evolution of 5,6-dihydroxypyrimidine-4-carboxamides and N-methyl-4-hydroxypyrimidinone-carboxamides, which exhibited potent inhibition of the HIV-integrase catalyzed strand transfer process. Structural modifications on these molecules were made in order to maximize potency as HIV-integrase inhibitors against the wild type virus, a selection of mutants, and optimize the selectivity, pharmacokinetic, and metabolic profiles in preclinical species. The good profile of Raltegravir has enabled its progression toward the end of phase III clinical trials for the treatment of HIV-1 infection and culminated with the FDA approval as the first HIV-integrase inhibitor for the treatment of HIV-1 infection.
The increasing incidence of resistance to current HIV-1 therapy underscores the need to develop antiretroviral agents with new mechanisms of action. Integrase, one of three viral enzymes essential ...for HIV-1 replication, presents an important yet unexploited opportunity for drug development. We describe here the identification and characterization of L-870,810, a small-molecule inhibitor of HIV-1 integrase with potent antiviral activity in cell culture and good pharmacokinetic properties. L-870,810 is an inhibitor with an 8-hydroxy-(1,6)-naphthyridine-7-carboxamide pharmacophore. The compound inhibits HIV-1 integrase-mediated strand transfer, and its antiviral activity in vitro is a direct consequence of this ascribed effect on integration. L-870,810 is mechanistically identical to previously described inhibitors from the diketo acid series; however, viruses selected for resistance to L-870,810 contain mutations (integrase residues 72, 121, and 125) that uniquely confer resistance to the naphthyridine. Conversely, mutations associated with resistance to the diketo acid do not engender naphthyridine resistance. Importantly, the mutations associated with resistance to each of these inhibitors map to distinct regions within the integrase active site. Therefore, we propose a model of the two inhibitors that is consistent with this observation and suggests specific interactions with discrete binding sites for each ligand. These studies provide a structural basis and rationale for developing integrase inhibitors with the potential for unique and nonoverlapping resistance profiles.
Naphthyridine 7 inhibits the strand transfer of the integration process catalyzed by integrase with an IC50 of 10 nM and inhibits 95% of the spread of HIV-1 infection in cell culture at 0.39 μM. It ...does not exhibit cytotoxicity in cell culture at ≤12.5 μM and shows a good pharmacokinetic profile when dosed orally to rats. The antiviral activity of 7 and its effect on integration were confirmed using viruses with specific integrase mutations.
Optimization studies using an HIV RNase H active site inhibitor containing a 1-hydroxy-1,8-naphthyridin-2(1H)-one core identified 4-position substituents that provided several potent and selective ...inhibitors. The best compound was potent and selective in biochemical assays (IC50=0.045μM, HIV RT RNase H; 13μM, HIV RT-polymerase; 24μM, HIV integrase) and showed antiviral efficacy in a single-cycle viral replication assay in P4-2 cells (IC50=0.19μM) with a modest window with respect to cytotoxicity (CC50=3.3μM).
HIV-1 integrase catalyzes the insertion of viral DNA into the genome of the host cell. Integrase inhibitor
N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide selectively inhibits the strand ...transfer process of integration. 4-Substituted pyrrolidinones possessing various groups on the pyrrolidinone nitrogen were introduced at the 5-position of the naphthyridine scaffold. These analogs exhibit excellent activity against viral replication in a cell-based assay. The preparation of these compounds was enabled by a three-step, two-pot reaction sequence from a common butenolide intermediate.
A series of 4-oxo-4,5,6,7-tetrahydropyrazolo1,5-
apyrazine-2-carboxamides was synthesized and tested for their inhibition of HIV-1 integrase catalytic activity and HIV-1 replication in cells. ...Structure–activity studies around lead compound
5 indicated that a coplanar relationship of metal-binding heteroatoms provides optimal binding to the integrase active site. Identification of potency-enhancing substituents and adjustments in lipophilicity provided
17b which inhibits integrase-catalyzed strand transfer with an IC
50 value of 74
nM and inhibits HIV-1 replication in cell culture in the presence of 50% normal human serum with an IC
95 value of 63
nM.
A series of 4-oxo-4,5,6,7-tetrahydropyrazolo1,5-
apyrazine-2-carboxamides was synthesized and tested for their inhibition of HIV-1 integrase catalytic activity and HIV-1 replication in cells. Structure–activity studies around lead compound
5 indicated that a coplanar relationship of metal-binding heteroatoms provides optimal binding to the integrase active site. Identification of potency-enhancing substituents and adjustments in lipophilicity provided
17b which inhibits integrase-catalyzed strand transfer with an IC
50 value of 74
nM and inhibits HIV-1 replication in cell culture in the presence of 50% normal human serum with an IC
95 value of 63
nM.
Display omitted
A series of 10-hydroxy-7,8-dihydropyrazino1′,2′:1,5pyrrolo2,3-
dpyridazine-1,9(2
H,6
H)-diones was synthesized and tested for their inhibition of HIV-1 replication in cell culture. ...Structure–activity studies indicated that high antiviral potency against wild-type virus as well as viruses containing integrase mutations that confer resistance to three different structural classes of integrase inhibitors could be achieved by incorporation of small aliphatic groups at certain positions on the core template. An optimal compound from this study,
16, inhibits integrase strand-transfer activity with an IC
50 value of ⩽10
nM, inhibits HIV-1 replication in cell culture with an IC
95 value of 35
nM in the presence of 50% normal human serum, and displays modest pharmacokinetic properties in rats (iv
t
1/2
=
5.3
h,
F
=
17%).
A potent and orally active HIV-1 integrase inhibitor Egbertson, Melissa S.; Moritz, H. Marie; Melamed, Jeffrey Y. ...
Bioorganic & medicinal chemistry letters,
03/2007, Letnik:
17, Številka:
5
Journal Article
Recenzirano
A 1,6-naphthyridine inhibitor of HIV-1 integrase has been discovered with excellent inhibitory activity in cells, good pharmacokinetics, and an excellent ability to inhibit virus with mutant enzyme.
We describe the efficacy of L-870812, an inhibitor of HIV-1 and SIV integrase, in rhesus macaques infected with the simian-human immunodeficiency virus (SHIV) 89.6P. When initiated before CD4 cell ...depletion, L-870812 therapy mediated a sustained suppression of viremia, preserving CD4 levels and permitting the induction of virus-specific cellular immunity. L-870812 was also active in chronic infection; however, the magnitude and durability of the effect varied in conjunction with the pretreatment immune response and viral load. These studies demonstrate integrase inhibitor activity in vivo and suggest that cellular immunity facilitates chemotherapeutic efficacy in retroviral infections.
Introduction of a 5,6-dihydrouracil functionality in the 5-position of
N-(4-fluorobenzyl)-8-hydroxy-1,6naphthyridine-7-carboxamide
1 led to a series of highly active HIV-1 integrase inhibitors. These ...compounds displayed low nanomolar activity in inhibiting both the strand transfer process of HIV-1 integrase and viral replication in cells. Compound
11 is a 150-fold more potent antiviral agent than
1, with a CIC
95 of 40
nM in the presence of human serum. It displays good pharmacokinetics when dosed in rats and dogs.
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