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Loviride (R 89439) Sale

(Synonyms: 洛韦胺,R 89439) 目录号 : GC32358

Loviride (R 89439) (R 89439) 是一种非核苷类逆转录酶抑制剂 (NNRTI),抑制 HIV-1 逆转录酶的 IC50 为 0.3 μM。

Loviride (R 89439) Chemical Structure

Cas No.:147362-57-0

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产品描述

Loviride (R 89439) is a non-nucleoside reverse transcriptase inhibitor (NNRTI), with IC50s of 0.3 µM for reverse transcriptase from HIV-1. Loviride (R 89439) inhibits HIV-1, HIV-2 and SIV replication in MT-4 cells[1].

Loviride (0.01 µM) inhibits HIV-1(IIIB) replication in MT-4 cells, also inhibits HIV-2 and SIV, with EC50s of 85.5, 7.4 µM for HIV-2 (ROD), HIV-2 (EHO), and 11.4, 28.5, 57.0 µM for SIV (mac251), SIV (agm3), SIV (mndGB1), respectively[1].

[1]. Witvrouw M, et al. Activity of non-nucleoside reverse transcriptase inhibitors against HIV-2 and SIV. AIDS. 1999 Aug 20;13(12):1477-83.

Chemical Properties

Cas No. 147362-57-0 SDF
别名 洛韦胺,R 89439
Canonical SMILES O=C(N)C(NC1=C(C(C)=O)C=CC(C)=C1)C2=C(Cl)C=CC=C2Cl
分子式 C17H16Cl2N2O2 分子量 351.23
溶解度 Soluble in DMSO 储存条件 Store at -20°C
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Research Update

Potent and highly selective human immunodeficiency virus type 1 (HIV-1) inhibition by a series of alpha-anilinophenylacetamide derivatives targeted at HIV-1 reverse transcriptase

Proc Natl Acad Sci U S A 1993 Mar 1;90(5):1711-5.PMID:7680476DOI:10.1073/pnas.90.5.1711.

In vitro evaluation of a large chemical library of pharmacologically acceptable prototype compounds in a high-capacity, cellular-based screening system has led to the discovery of another family of human immunodeficiency virus type 1 (HIV-1) inhibitors. Through optimization of a lead compound, several alpha-anilinophenylacetamide (alpha-APA) derivatives have been identified that inhibit the replication of several HIV-1 strains (IIIB/LAI, RF, NDK, MN, HE) in a variety of host cell types at concentrations that are 10,000- to 100,000-fold lower than their cytotoxic concentrations. The IC50 of the alpha-APA derivative R 89439 for HIV-1 cytopathicity in MT-4 cells was 13 nM. The median 90% inhibitory concentration (IC90) in a variety of host cells was 50-100 nM. Although these alpha-APA derivatives are active against a tetrahydroimidazo [4,5,1-jk][1,4]benzodiazepin-2(1H)-thione-(TIBO)-resistant HIV-1 strain, they do not inhibit replication of HIV-2 (strains ROD and EHO) or simian immunodeficiency virus (strains Mac251, mndGB1, and agm3). An HIV-1 strain containing the Tyr181-->Cys mutation in the reverse transcriptase region displayed reduced sensitivity. alpha-APA derivative R 89439 inhibited virion and recombinant reverse transcriptase of HIV-1 but did not inhibit that of HIV-2. Reverse transcriptase inhibition depended upon the template/primer used. The relatively uncomplicated synthesis of R 89439, its potent anti-HIV-1 activity, and its favorable pharmacokinetic profile make R 89439 a good candidate for clinical studies.

Drug precipitation-permeation interplay: supersaturation in an absorptive environment

Eur J Pharm Biopharm 2012 Oct;82(2):424-8.PMID:22841881DOI:10.1016/j.ejpb.2012.07.009.

Purpose: The present study investigated the interplay between supersaturation, absorption, precipitation, and excipient-mediated precipitation inhibition by comparing classic precipitation assessment in a non-absorption environment with precipitation/permeation assessment in an absorption environment. Loviride and HPMC-E5 were selected as poorly soluble model drug and precipitation inhibitor, respectively. Method: To investigate supersaturation in an absorptive environment, supersaturation was induced at different degrees (DS), using a solvent shift method, in shaken Caco-2 Transwell庐 inserts containing fasted state simulated intestinal fluid (FaSSIF); to simulate a non-absorption environment, the inserts were parafilm-sealed and did not contain a cell monolayer. Donor and acceptor compartments were sampled as a function of time to determine precipitation kinetics and transport, respectively. Results: In absence of precipitation, Loviride transport increased proportionally with the initial DS; however, precipitation limited the supersaturation-induced transport enhancement. Loviride precipitation was found to be less extensive in an absorption environment compared to a non-absorption environment. As a result, the optimal DS obtained in a non-absorption environment (highest amount maintained in solution) did not correlate with the highest transport in an absorption environment. In addition, the impact of HPMC-E5 on Loviride transport was inferior to its precipitation inhibitory capacity observed in a non-absorption environment. Conclusion: For the first time, the present study explicitly demonstrated that implementation of permeation in precipitation assays is critical to predict the impact of supersaturation, precipitation, and precipitation inhibition on the absorption of poorly soluble drugs.

Perspectives of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection

Farmaco 1999 Jan-Feb;54(1-2):26-45.PMID:10321027DOI:10.1016/s0014-827x(98)00103-7.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have, in addition to the nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs), gained a definitive place in the treatment of HIV-1 infections. Starting from the HEPT and TIBO derivatives, more than thirty structurally different classes of compounds have been identified as NNRTIs, that is compounds that are specifically inhibitory to HIV-1 replication and targeted at the HIV-1 reverse transcriptase (RT). Two NNRTIs (nevirapine and delavirdine) have been formally licensed for clinical use and several others are (or have been) in preclinical and/or clinical development [tivirapine (TIBO R-86183), Loviride (alpha-APA R89439), thiocarboxanilide UC-781, HEPT derivative MKC-442, quinoxaline HBY 097, DMP 266 (efavirenz), PETT derivatives (trovirdine, PETT-4, PETT-5) and the dichlorophenylthio(pyridyl)imidazole derivative S-1153]. The NNRTIs interact with a specific 'pocket' site of HIV-1 RT that is closely associated with, but distinct from, the NRTI binding site. NNRTIs are notorious for rapidly eliciting resistance due to mutations of the amino acids surrounding the NNRTI-binding site. However, the emergence of resistant HIV strains can be circumvented if the NNRTIs, preferably in combination with other anti-HIV agents, are used from the start at sufficiently high concentrations. In vitro, this procedure has been shown to 'knock-out' virus replication and to prevent resistance from arising. In vivo, various triple-drug combinations containing NNRTIs, NRTIs and/or PIs may result in an effective viral suppression and ensuing immune recovery. However, this so-called HAART (highly active antiretroviral therapy) may also fail, and this necessitates the design of new and more effective drugs and drug cocktails.

Characterization of physico-chemical properties and pharmaceutical performance of sucrose co-freeze-dried solid nanoparticulate powders of the anti-HIV agent Loviride prepared by media milling

Int J Pharm 2007 Jun 29;338(1-2):198-206.PMID:17363200DOI:10.1016/j.ijpharm.2007.02.005.

In order to improve the dissolution and absorption properties of Loviride, a poorly soluble antiviral agent, sucrose co-freeze-dried nanopowders were prepared, characterized and evaluated. Tween 80/poloxamer 188-stabilized nanosuspensions were produced on a laboratory scale using media milling. The milling process was monitored by dynamic light scattering (DLS) and resulted in particles with a mean size of 264+/-14nm and a distribution width of 59+/-6nm after 4h of milling. Co-freeze-drying of the nanosuspensions with sucrose had an inhibiting effect on nanoparticle agglomeration and yielded solid "nanopowders" that were resuspendable and homogeneous with respect to Loviride content. X-ray powder diffraction (XRPD) confirmed the presence of small Loviride crystallites and indicated that sucrose and poloxamer 188 were crystalline. Differential scanning calorimetry (DSC) showed melting peaks of poloxamer 188, sucrose and Loviride. Time-resolved XRPD indicated that sucrose crystallization was complete within 24h of storage. Scanning electron microscopy (SEM) suggested the formation of sheet-like matrix structures. The dissolution rate of Loviride from the nanopowders was excellent. A Caco-2 experiment on the nanopowder showed a significantly higher cumulative amount transported after 120min (1.59+/-0.02microg) compared to the physical mixture (0.93+/-0.01microg) and the untreated Loviride (0.74+/-0.03mcirog).

Complete inhibition of viral breakthrough by combination of MKC-442 with AZT during a long-term culture of HIV-1 infected cells

Antiviral Res 1996 Jun;31(1-2):69-77.PMID:8793010DOI:10.1016/0166-3542(96)00946-1.

We have investigated viral breakthrough during a long-term culture of HIV-1-infected cells with the non-nucleoside reverse transcriptase inhibitors (NNRTIs) 6-benzyl-1-ethoxymethyl-5-isopropyluracil (MKC-442), nevirapine and Loviride (alpha-APA). When the compounds were examined for their inhibitory effects on HIV-1 (HE strain) replication in MT-4 cells on day 4 after virus infection, the 50% effective concentrations (EC50) of MKC-442, nevirapine and Loviride were 9.4, 98 and 21 nM, respectively. After a 48-day culture period, MKC-442, nevirapine and Loviride completely inhibited viral breakthrough at concentrations of 1, 5 and 1 microM, respectively. These concentrations were 50-100-fold higher than their EC50 values. When the cells were treated with either MKC-442 (0.04 and 0.2 microM), nevirapine (0.2 and 1 microM) or Loviride (0.04 and 0.2 microM) in combination with AZT (0.005 microM), only the combination of 0.2 microM MKC-442 with 0.005 microM AZT could completely inhibit the breakthrough of HIV-1 after a 68-day culture period. Polymerase chain reaction (PCR) analysis revealed that no proviral DNA was detected in the cells treated with this combination. Except for two combinations (0.04 microM MKC-442 + 0.005 microM AZT and 0.04 microM Loviride + 0.005 microM AZT), all of the viruses isolated during combination treatments had various amino acid mutations in their reverse transcriptase (RT). These results indicate that the combination treatment with a relatively high dose of MKC-442 and a low dose of AZT may have potential to suppress the emergence of drug resistance during a long-term treatment in vivo and should be further pursued in HIV-1-infected patients.