Details
| Stereochemistry | ACHIRAL |
| Molecular Formula | C19H18FN3O4 |
| Molecular Weight | 371.3623 |
| Optical Activity | NONE |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
CN1C(=O)C(C(=O)NCCO)=C(O)C2=NC=C(CC3=CC=C(F)C=C3)C=C12
InChI
InChIKey=QWLNINWUBHHOLU-UHFFFAOYSA-N
InChI=1S/C19H18FN3O4/c1-23-14-9-12(8-11-2-4-13(20)5-3-11)10-22-16(14)17(25)15(19(23)27)18(26)21-6-7-24/h2-5,9-10,24-25H,6-8H2,1H3,(H,21,26)
| Molecular Formula | C19H18FN3O4 |
| Molecular Weight | 371.3623 |
| Charge | 0 |
| Count |
|
| Stereochemistry | ACHIRAL |
| Additional Stereochemistry | No |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Optical Activity | NONE |
GlaxoSmithKline was developing GSK-364735 as a human immunodeficiency virus (HIV) integrase inhibitor. The inhibition of viral DNA integration takes place by interacting at the two-metal binding site within the catalytic center of HIV integrase. GSK-364735 was successfully studied at Phase II in HIV-infected patients; however, adverse liver effects of GSK364735 were recently observed in a long-term preclinical safety study in the monkey and preclude further development of the compound.
Originator
Approval Year
PubMed
| Title | Date | PubMed |
|---|---|---|
| Safety and pharmacokinetics of GSK364735, a human immunodeficiency virus type 1 integrase inhibitor, following single and repeated administration in healthy adult subjects. | 2007 Dec |
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| Mirabamides A-D, depsipeptides from the sponge Siliquariaspongia mirabilis that inhibit HIV-1 fusion. | 2007 Nov |
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| The naphthyridinone GSK364735 is a novel, potent human immunodeficiency virus type 1 integrase inhibitor and antiretroviral. | 2008 Mar |
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| Potent inhibitors of HIV-1 integrase display a two-step, slow-binding inhibition mechanism which is absent in a drug-resistant T66I/M154I mutant. | 2009 Feb 24 |
Patents
Sample Use Guides
In part A, three alternating cohorts of 10 subjects (8 receiving the active drug and 2 receiving a placebo) received single doses of 50 to 400 mg while fasting or 200 mg and 400 mg coadministered with food. In part B, five cohorts received repeated doses of 100 to 600 mg daily coadministered with food for 8 days.
Route of Administration:
Oral
| Substance Class |
Chemical
Created
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SXN0KXT60S
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Validated (UNII)
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ACTIVE MOIETY |
Class: Antiretroviral; Mechanism of Action: HIV integrase inhibitor; Highest Development Phase: Discontinued for HIV infections; Most Recent Events: 30 Jul 2007 Discontinued - Phase-II for HIV infections treatment in USA (PO), 12 Mar 2007 Clinical data presented at the 14th Conference on Retroviruses and Opportunistic Infections (CROI-2007) added to the adverse events and pharmacokinetics section, 31 Oct 2006 Phase-II clinical trials in HIV infections treatment in USA (PO)
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ACTIVE MOIETY |
The naphthyridinone GSK364735 potently inhibited recombinant human immunodeficiency virus type 1 (HIV-1) integrase in a strand transfer assay (mean 50% inhibitory concentration +/- standard deviation, 8 +/- 2 nM). As expected based on the structure of the drug, it bound competitively with another two-metal binding inhibitor (Kd (binding constant), 6 +/- 4 nM). In a number of different cellular assays, GSK364735 inhibited HIV replication with potency at nanomolar concentrations (e.g., in peripheral blood mononuclear cells and MT-4 cells, 50% effective concentrations were 1.2 +/- 0.4 and 5 +/- 1 nM, respectively), with selectivity indexes of antiviral activity versus in-assay cytotoxicity of at least 2,200. When human serum was added, the antiviral potency decreased (e.g., a 35-fold decrease in the presence of 100% human serum was calculated by extrapolation from the results of the MT-4 cell assay).
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