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
Rapidly absorbed
Delavirdine is extensively converted to several inactive metabolites by cytochrome P450 3A (CYP3A). Delavirdine was excreted in the milk of lactating rats at a concentration three to five times that of rat plasma.

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Metabolism / Metabolites
Hepatic
Delavirdine has known human metabolites that include N-Desisopropyl delavirdine and N-[2-[4-[6-oxo-3-(propan-2-ylamino)-1H-pyridin-2-yl]piperazine-1-carbonyl]-1H-indol-5-yl]methanesulfonamide.

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Biological Half-Life
5.8 hours

Hepatotoxicity
Serum aminotransferase elevations occur in 25% or more of patients on delavirdine therapy, but rise above 5 times the upper limit of normal in 4% or less; this rate is higher in patients who have chronic hepatitis C coinfection. Clinically apparent hepatotoxicity due to delavirdine must be rare, as individual case reports of hepatitis or jaundice have not been published. Nevertheless, cases of hepatitis, jaundice and hepatic failure have been reported to the sponsor and are mentioned in the product label. The liver injury may be immunoallergic and similar in pattern to that attributed to nevirapine and efavirenz. In immunoallergic hepatitis due to nonnucleoside reverse transcriptase inhibitors, injury usually arises within 1 to 8 weeks of starting therapy. Signs of hypersensitivity are common including rash, fever, and eosinophilia and sometimes facial edema, lymphadenoapthy and lymphocytosis. The serum enzyme pattern can be cholestatic, hepatocellular or mixed. Recovery is rapid upon stopping therapy.
Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).

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Protein Binding
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 the amide resulting from the formal condensation of 5-[(methylsulfonyl)amino]-1H-indole-2-carboxylic acid and 4-amino group of 1-[3-(isopropylamino)pyridin-2-yl]piperazine, delavirdine is a non-nucleoside reverse transcriptase inhibitor with activity specific for HIV-1. Viral resistance emerges rapidly when delavirdine is used alone, so it is therefore used (as the methanesulfonic acid salt) with other antiretrovirals for combination therapy of HIV infection. It has a role as a HIV-1 reverse transcriptase inhibitor and an antiviral drug. It is a N-acylpiperazine, a sulfonamide, an aminopyridine and an indolecarboxamide.
A potent, non-nucleoside reverse transcriptase inhibitor with activity specific for HIV-1.
Delavirdine is a Human Immunodeficiency Virus 1 Non-Nucleoside Analog Reverse Transcriptase Inhibitor. The mechanism of action of delavirdine is as a Non-Nucleoside Reverse Transcriptase Inhibitor.
Delavirdine is a nonnucleoside reverse transcriptase inhibitor used in combination with other agents in the therapy of human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS). Delavirdine is associated with a low rate of transient serum aminotransferase elevations during therapy and is a rare cause of clinically apparent acute liver injury.
Delavirdine is a synthetic, non-nucleoside reverse transcriptase inhibitor. In combination with other anti-retroviral drugs, this agent has been shown to reduce HIV viral load and increase CD4 leukocyte counts in patients. As an inhibitor of the cytochrome P450 system, delavirdine may result in increased serum levels of co-administered protease inhibitors metabolized by the cytochrome P450 system.
A potent, non-nucleoside reverse transcriptase inhibitor with activity specific for HIV-1.
See also: Delavirdine Mesylate (annotation moved to).

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Drug Indication
For the treatment of HIV-1 infection in combination with appropriate antiretroviral agents when therapy is warranted
FDA Label

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Mechanism of Action
Delavirdine binds directly to viral reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by disrupting the enzyme's catalytic site.

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Pharmacodynamics
Delavirdine is a non-nucleoside reverse transcriptase inhibitor (nNRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Delavirdine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. The activity of Delavirdine does not compete with template or nucleoside triphosphates. HIV-2 RT and eukaryotic DNA polymerases (such as human DNA polymerases alpha, beta, or sigma) are not inhibited by Delavirdine.

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.)