Delavirdine targets HIV-1 reverse transcriptase, an enzyme essential for the replication of HIV. As a non-nucleoside reverse transcriptase inhibitor (NNRTI), delavirdine binds to an allosteric site on reverse transcriptase, distinct from the active site where nucleoside analogs bind. This binding induces a conformational change in the enzyme that inhibits its polymerase activity, thereby blocking the conversion of viral RNA into DNA and preventing viral replication. Delavirdine is specific for HIV-1 and does not inhibit HIV-2 or other retroviruses.

Delavirdine was 50% cytotoxic at doses greater than 100 μM in H9 and PBMC cells. At 100 μM, delavirdine has minimal cytotoxicity, resulting in a reduction of less than 8% in the viability of peripheral blood lymphocytes [1]. Delavirdine has an IC50 value of 0.26 μM for wild-type HIV-1 reverse transcriptase (RT) and IC50 values of 8.32 uM and 7.7 uM for Y181C-substituted and K103N-substituted RT, respectively [1].
In vitro, delavirdine acts as a potent inhibitor of HIV-1 reverse transcriptase with activity specific for HIV-1. Its ability to inhibit HIV-1 replication has been demonstrated in cell-based assays using HIV-1-infected cell lines. The compound exhibits potent antiviral activity against various HIV-1 strains, including those resistant to other NNRTIs. Delavirdine shows low cytotoxicity in vitro. Its antiviral activity has been characterized in numerous preclinical studies.

Delavirdine (U 90152) (oral gavage; 10 mg/kg, 200 mg/kg, 250 mg/kg; single dose) is rapidly absorbed and digested, forms a tiny circulating component, and has peculiar pharmacokinetics. Linear and has limited or inhibited metabolism to dealkylavirdine in CD-1 mice (PK study) [1].
In vivo, delavirdine is used as part of highly active antiretroviral therapy (HAART) for the treatment of HIV-1 infection in adults and adolescents over age 16. It is approved for use in combination with other antiretroviral agents. Clinical studies have demonstrated its efficacy in reducing viral load and increasing CD4+ T cell counts. The compound is marketed under the brand name Rescriptor. Delavirdine is typically used in combination with nucleoside reverse transcriptase inhibitors and protease inhibitors.

In vitro enzyme/receptor binding assays for delavirdine are reverse transcriptase inhibition assays using purified HIV-1 reverse transcriptase enzyme. The enzyme is incubated with a template-primer and nucleotide substrates in the presence of varying concentrations of delavirdine, and the extent of DNA synthesis is measured using radioactive or fluorescent methods. The IC50 for inhibition of reverse transcriptase activity is determined from dose-response curves.

In vitro cellular assays for delavirdine are performed using HIV-1-infected cell lines, such as MT-4 or CEM cells. Cells are infected with HIV-1 and treated with varying concentrations of delavirdine. Viral replication is assessed by measuring the production of viral p24 antigen or reverse transcriptase activity in the culture supernatant. Cytotoxicity is evaluated using MTT assays to determine the selectivity index. These assays confirm the compound's ability to inhibit HIV-1 replication in cells.

In vivo animal experiments for delavirdine are limited because HIV-1 does not infect standard laboratory animals. However, efficacy studies have been conducted in HIV-1-infected humanized mouse models or in clinical trials in humans. In clinical studies, patients are treated with delavirdine in combination with other antiretroviral agents, and viral load and CD4+ T cell counts are monitored. These studies have demonstrated the compound's efficacy in treating HIV-1 infection.

Absorption, Distribution and Excretion
Rapid Absorption Deraviridine is primarily converted into various inactive metabolites via cytochrome P450 3A (CYP3A). The concentration of deraviridine in the milk of lactating rats is three to five times higher than its plasma concentration. Metabolism/Metabolites Hepatic Metabolism Known human metabolites of deraviridine include N-deisopropylidene deraviridine and N-[2-[4-[6-oxo-3-(propyl-2-amino)-1H-pyridin-2-yl]piperazin-1-carbonyl]-1H-indol-5-yl]methanesulfonamide. Biological Half-Life 5.8 hours
Delavirdine has a molecular weight of 457.55 g/mol and a molecular formula of C22H28N6O3S. The compound is orally bioavailable and is formulated for oral administration. Detailed pharmacokinetic parameters such as half-life, Cmax, and bioavailability have been characterized in clinical studies. Delavirdine is metabolized in the liver primarily by CYP3A4 and has a relatively short half-life. It is a substrate and inhibitor of CYP3A4, which can lead to drug-drug interactions.

Hepatotoxicity
In patients receiving deraviridine, elevated serum transaminases occur in 25% or more of cases, but only 4% or fewer have transaminases elevated to more than 5 times the upper limit of normal; this proportion is even higher in patients with concurrent chronic hepatitis C virus infection. Clinically significant hepatotoxicity caused by deraviridine should be rare, as there are no reported cases of hepatitis or jaundice. Nevertheless, the sponsor has received case reports of hepatitis, jaundice, and liver failure, which are mentioned in the product information leaflet. Liver injury may be immunoallergic, following a pattern similar to that caused by nevirapine and efavirenz. Immunohistotropic hepatitis caused by non-nucleoside reverse transcriptase inhibitors usually appears within 1 to 8 weeks after the start of treatment. Common symptoms of allergic reactions include rash, fever, and eosinophilia, sometimes accompanied by facial edema, lymphadenopathy, and lymphocytosis. Serum enzyme profiles may show cholestatic, hepatocellular, or mixed patterns. Recovery is rapid upon discontinuation of the drug.
Probability Score: E (Unconfirmed but suspected cause of clinically significant liver damage).

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Protein Binding Rate
98%
Delavirdine has been evaluated in clinical studies and has been reported to be generally well-tolerated. Common adverse effects include rash, which usually resolves within several weeks of treatment. Severe skin reactions are rare. Other adverse effects may include gastrointestinal disturbances, headache, and elevated liver enzymes. Delavirdine is contraindicated in patients with severe hepatic impairment and those taking certain medications that interact with CYP3A4.

[1]. U-90152, a potent inhibitor of human immunodeficiency virus type 1 replication. Antimicrob Agents Chemother. 1993 May;37(5):1127-31.

[2]. Metabolism of the HIV-1 Reverse Transcriptase Inhibitor Delavirdine In Mice. Research Article.

Delavirdine is an amide formed by the condensation of the 4-amino group of 5-[(methanesulfonyl)amino]-1H-indole-2-carboxylic acid and 1-[3-(isopropylamino)pyridin-2-yl]piperazine. Delavirdine is a non-nucleoside reverse transcriptase inhibitor with specific activity against HIV-1. Viral resistance develops rapidly when Delavirdine is used alone; therefore, it is often used in combination with other antiretroviral drugs for the treatment of HIV infection (in the form of mesylate). It is both an HIV-1 reverse transcriptase inhibitor and an antiviral drug. It is an N-acylpiperazine, sulfonamide, aminopyridine, and indolecarboxamide compound. It is a potent non-nucleoside reverse transcriptase inhibitor with specific activity against HIV-1. Delavirdine is a non-nucleoside analog reverse transcriptase inhibitor of human immunodeficiency virus type 1. The mechanism of action of Delavirdine is as a non-nucleoside reverse transcriptase inhibitor.
Dilaviridine is a non-nucleoside reverse transcriptase inhibitor used in combination with other drugs to treat human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS). The incidence of transient elevations in serum transaminases during ilaviridine treatment is low, and it rarely causes clinically significant acute liver injury.
Dilaviridine is a synthetic non-nucleoside reverse transcriptase inhibitor. When used in combination with other antiretroviral drugs, it has been shown to reduce HIV viral load and increase CD4 white blood cell counts in patients. As an inhibitor of the cytochrome P450 system, ilaviridine may lead to elevated serum concentrations of co-administered protease inhibitors metabolized by the cytochrome P450 system.
A potent non-nucleoside reverse transcriptase inhibitor with specific activity against HIV-1.
See also: Dilaviridine mesylate (note moved to).

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Drug Indications
For the treatment of HIV-1 infection in combination with an appropriate antiretroviral drug when treatment is required.
FDA Label
Mechanism of Action
Dilaviridine binds directly to viral reverse transcriptase (RT) and blocks RNA-dependent and DNA-dependent DNA polymerase activity by disrupting the enzyme's catalytic site.
Pharmacodynamics
Dilaviridine is a non-nucleoside reverse transcriptase inhibitor (nNRTI) active against human immunodeficiency virus type 1 (HIV-1). Deilaviridine binds directly to reverse transcriptase (RT) and blocks RNA-dependent and DNA-dependent DNA polymerase activity by disrupting the enzyme's catalytic site. Deilaviridine's activity does not compete with the template or nucleoside triphosphates. HIV-2 reverse transcriptase and eukaryotic DNA polymerases (such as human DNA polymerase α, β, or σ) are not inhibited by deilaviridine.
Delavirdine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used as part of highly active antiretroviral therapy (HAART) for the treatment of HIV-1 infection. It is marketed under the brand name Rescriptor and is approved for use in adults and adolescents over age 16. Delavirdine is a bisheteroarylpiperazine derivative with potent activity specific for HIV-1. It is used in combination with other antiretroviral agents. Delavirdine is metabolized by CYP3A4 and can cause drug-drug interactions.

C22H28N6O3S

456.56

456.194

136817-59-9

Delavirdine mesylate;147221-93-0

5625

White to off-white solid powder

1.388g/cm3

732ºC at 760mmHg

226-228ºC

396.5ºC

2.74E-21mmHg at 25°C

1.68

3.946

3

7

6

32

749

0

O=S(NC1=CC=C(NC(C(N2CCN(C3=C(NC(C)C)C=CC=N3)CC2)=O)=C4)C4=C1)(C)=O

WHBIGIKBNXZKFE-UHFFFAOYSA-N

InChI=1S/C22H28N6O3S/c1-15(2)24-19-5-4-8-23-21(19)27-9-11-28(12-10-27)22(29)20-14-16-13-17(26-32(3,30)31)6-7-18(16)25-20/h4-8,13-15,24-26H,9-12H2,1-3H3

N-[2-[4-[3-(propan-2-ylamino)pyridin-2-yl]piperazine-1-carbonyl]-1H-indol-5-yl]methanesulfonamide

BHAP-U 90152; DLV; U 90152; Delavirdine; trade name Rescriptor.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)