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].

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].

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

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%

[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.

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

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.)