Human Immunodeficiency Virus Type 1 (HIV-1) Reverse Transcriptase (RT) (IC₅₀ = 0.26 μM for recombinant HIV-1 RT)
DNA polymerase α (IC₅₀ > 440 μM)
DNA polymerase δ (IC₅₀ > 550 μM)

Delavirdine was 50% cytotoxic in H9 and PBMC cells at doses greater than 100 μM. At 100 μM, delavirdine causes less than 8% reduction in peripheral blood lymphocyte viability, indicating its modest cytotoxicity [1]. With an IC50 value of 0.26 μM, delavirdine inhibits HIV-1 reverse transcriptase (RT) in its wild-type form. It also inhibits RT replaced with Y181C and K103N, with IC50 values of 8.32 uM and 7.7 uM, respectively [1].

---

U-90152 inhibited recombinant HIV-1 reverse transcriptase with an IC₅₀ of 0.26 μM, showing high selectivity over cellular DNA polymerases α and δ (IC₅₀ > 440 μM and >550 μM, respectively).
It blocked the replication of 25 primary HIV-1 isolates in peripheral blood lymphocytes with a mean ED₅₀ of 0.066 ± 0.137 μM, including variants resistant to AZT or ddI.
At 100 μM, it caused less than 8% reduction in peripheral blood lymphocyte viability.
In MT-2 cells, it inhibited HIV-1-induced syncytia formation with an ED₅₀ of about 10 nM.
In primary monocyte-macrophage cultures infected with monocytotropic HIV-1_JR-FL, it showed an ED₅₀ of approximately 20 nM.
It completely prevented the spread of HIV-1_IIIB in MT-4 cell co-cultures at 3 μM, and in combination with 0.5 μM AZT, it also totally prevented viral spread.
It retained inhibitory activity against HIV-1 RT mutants Y181C (IC₅₀ = 8.32 μM) and K103N (IC₅₀ = 7.70 μM). [1]

Delavirdine (U 90152) mesylate is a small circulating component that is quickly absorbed and digested. It is administered orally as a single dosage at 10 mg/kg, 200 mg/kg, or 250 mg/kg. Its capacity to metabolize to dealkylavirdine is restricted or hindered in CD-1 mice (PK research), and its metabolic kinetics are non-linear [1].

The inhibition of recombinant heterodimeric HIV-1 RT derived from HIV-1_IIIB by U-90152 was assayed using a previously described method with highly purified enzyme. Inhibition of DNA polymerases α and δ was assayed using poly(dA)-oligod(dT) as the template-primer, with proliferating cell nuclear antigen included in the polymerase δ assay. Drug-resistant mutant RTs (Y181C, K103N) were prepared by site-directed mutagenesis, cloned into an expression plasmid, purified via metal affinity chromatography as p66 homodimers, and their RNA-dependent DNA polymerase activity was assayed in the presence of inhibitors. [1]

Antiviral activity against HIV-1_IIIB was assayed in MT-2 cells and primary peripheral blood lymphocytes (PBL). MT-2 cells were infected with HIV-1_IIIB, washed, and cultured with drug for 4 days; ED₅₀ was determined by syncytia counting. PBL were similarly infected and cultured for 6 days; viral replication was assessed by measuring supernatant p24 antigen levels.
Susceptibility testing against 25 clinical isolates used a standardized protocol: PBL were infected and cultured with drug, and p24 levels were measured.
Cytotoxicity was assayed by culturing phytohemagglutinin-stimulated normal PBL with 0 to 100 μM U-90152 for 7 days, followed by cell counting and viability determination via trypan blue exclusion.
Activity against monocytotropic HIV-1_JR-FL was determined in primary monocyte-macrophage cultures.
Inhibition of viral spread was assessed by co-cultivating HIV-1_IIIB-infected MT-4 cells with a 1000-fold excess of uninfected MT-4 cells in the presence of drug. Cultures were diluted periodically with fresh drug-containing medium. Viral spread was monitored via syncytia formation, p24 antigen levels, and cell viability. [1]

Absorption, Distribution and Excretion
Excretion: Fecal excretion: In healthy volunteers, after taking 330 mg three times daily, 44% of the drug was excreted in the feces. Renal excretion: In healthy volunteers, after taking 330 mg three times daily, 51% of the drug was excreted in the kidneys. Less than 5% of the drug was excreted unchanged in the urine. Delavoridine is primarily distributed in the plasma. Delavoridine is well absorbed, especially at pH values below 2.0. Oral absorption of delavoridine mesylate is rapid, reaching peak plasma concentration approximately 1 hour after administration. Following oral administration of 400 mg deraviridine mesylate three times daily in HIV-infected adults, the mean steady-state peak plasma concentration was 15.98 μg/mL (range: 0.91–45.66 μg/mL), the mean trough plasma concentration was 6.85 μg/mL (range: 0.05–20.55 μg/mL), and the mean AUC was 82.19 μg/h/mL. For more complete data on absorption, distribution, and excretion of deraviridine mesylate (8 items in total), please visit the HSDB record page. Metabolites/Metabolites: Deraviridine is extensively bound to plasma proteins and is primarily metabolized via CYP3A4. The main metabolic pathway is N-dealkylation. Significant inter-individual variability exists in plasma deraviridine concentrations, which is related to differences in CYP3A activity. The cerebrospinal fluid to plasma concentration ratio is 0.02.
Delavedin undergoes extensive metabolism in mice, including amide bond cleavage, N-dealkylation, pyridine ring C-6' hydroxylation, and pyridine ring cleavage. These metabolic pathways were determined by mass spectrometry and/or ¹H and ¹³C nuclear magnetic resonance spectroscopy. At low doses, N-dealkylation and amide bond cleavage are the predominant metabolic pathways; however, at high doses and after repeated administration, amide bond cleavage becomes the predominant metabolic pathway as the bioconversion of dealkylated delavedin reaches saturation or is inhibited.
Biological Half-Life
The apparent plasma half-life of delavedin increases with increasing dose. In adults, the mean plasma half-life after three daily doses of 400 mg delavedin is 5.8 hours (range: 2–11 hours).
Plasma Clearance: The mean clearance time after three daily doses of 400 mg is 5.8 hours (range: 2–11 hours). The apparent half-life increases with increasing dosage.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Delapiridine has been discontinued in the United States. There is currently no publicly available information regarding the use of delapiridine during lactation. Use of delapiridine during lactation is not recommended. Achieving and maintaining viral suppression through antiretroviral therapy can reduce the risk of transmission through breastfeeding to below 1%, but not zero. For HIV-infected individuals receiving antiretroviral therapy with a persistently low viral load below the detection limit, breastfeeding should be supported if they choose to do so. If viral load is not suppressed, pasteurized donor breast milk or formula is recommended.
◉ Effects on Breastfed Infants
No published information was found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information was found as of the revision date.

---

U-90152 showed low cytotoxicity. At a concentration of 100 μM, it resulted in a decrease of less than 8% in the viability of phytohemagglutinin-stimulated peripheral blood lymphocytes cultured for 7 days. [1]

[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.

Delavoridine mesylate is the monomethylsulfonate salt of delavoridine, a non-nucleoside reverse transcriptase inhibitor with specific activity against HIV-1. Viral resistance develops rapidly when delavoridine is used alone; therefore, it (in mesylate form) is often used in combination with other antiretroviral drugs for the treatment of HIV infection. It is both an antiviral drug and an HIV-1 reverse transcriptase inhibitor. It contains delavoridine. Delavoridine mesylate is the mesylate salt form of delavoridine, a synthetic non-nucleoside reverse transcriptase inhibitor. Studies have shown that when used in combination with other antiretroviral drugs, this drug can reduce HIV viral load and increase CD4 white blood cell counts in patients. As an inhibitor of the cytochrome P450 system, delavoridine may lead to increased 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.

---

Mechanism of Action
After entering the cell, delavide binds to the hydrophobic pocket of the p66 subunit of reverse transcriptase. This causes a conformational change in the enzyme, forming a stable, inactive form. The delavide-reverse transcriptase complex is stabilized by a hydrogen bond at lysine 103 residues and a strong hydrophobic interaction with proline 236 residues. The concentration of delavide required to inhibit cellular polymerase is much higher than the concentration required to inhibit reverse transcriptase.
Although the mechanism of delavide's antiviral activity is not fully elucidated, the drug inhibits the replication of human immunodeficiency virus type 1 (HIV-1) by interfering with the viral RNA and DNA polymerase activities of reverse transcriptase. HIV reverse transcriptase is crucial for viral replication; its activity occurs after the viral particle penetrates the cell membrane and releases the viral core, but before the virus enters the nucleus and integrates into the chromosome, it resides in the cytoplasm of the host cell. This enzyme is multifunctional, with three main activities: RNA-directed DNA polymerase, RNase H, and DNA-directed DNA polymerase. Reverse transcriptase uses viral RNA as a template to form the negative strand of viral DNA, thereby producing a double-stranded RNA:DNA hybrid (i.e., RNA-directed DNA polymerase function). The RNase H function of reverse transcriptase promotes viral RNA replication by degrading the RNA component in the RNA:DNA hybrid after RNA replication, leaving behind single-stranded viral DNA. Using the newly formed negative strand of viral DNA as a template, reverse transcriptase synthesizes the positive strand of viral DNA, converting the single-stranded viral DNA into a double-stranded proviral DNA form (i.e., DNA-directed DNA polymerase function). BHAP derivatives, including delavide, inhibit the polymerase function of reverse transcriptase but not its RNase H function. These drugs bind directly to heterodimeric HIV-1 reverse transcriptase, exerting antiviral effects as specific, non-competitive HIV-1 reverse transcriptase inhibitors. Non-nucleoside reverse transcriptase inhibitors act on different sites of reverse transcriptase, unlike nucleoside reverse transcriptase inhibitors (e.g., abacavir, didanoxin, lamivudine, stavudine, zalcitabine, zidovudine), and their mechanisms of action also differ. Unlike currently available non-nucleoside reverse transcriptase inhibitors, dideoxynucleoside antiretroviral drugs need to be converted into triphosphate metabolites within the cell. These metabolites then compete with naturally occurring deoxynucleoside triphosphates for reverse transcriptase incorporation into viral DNA, leading to premature termination of the viral DNA chain by preventing further 5'→3' phosphodiester bond formation. U-90152 is a novel biheteroarylpiperazine (BHAP) class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). Its structure is similar to U-87201E, but it exhibits higher antiviral activity.
It binds to HIV-1 reverse transcriptase at the same site as other BHAP and NNRTI drugs (such as nevirapine) and has a high epigenetic affinity (~80 nM).
Its inhibitory mechanism is a non-competitive inhibition against template-primer and substrate.
It exhibits synergistic inhibition of HIV-1 replication. When used in combination with AZT.
Although HIV-1 variants carrying RT mutations (e.g., Y181C, K103N) may exhibit lower sensitivity, U-90152 still maintains significant activity against these variants compared to other non-nucleoside reverse transcriptase inhibitors (NNRTIs).
Clinical trials of U-90152 mesylate have been initiated. [1]

C22H28N6O3S.CH4O3S

552.66678

552.182

147221-93-0

Delavirdine;136817-59-9

441386

White to yellow solid powder

732ºC at 760mmHg

118-120ºC

396.5ºC

2.74E-21mmHg at 25°C

4.531

4

10

6

37

842

0

MEPNHSOMXMALDZ-UHFFFAOYSA-N

InChI=1S/C22H28N6O3S.CH4O3S/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;1-5(2,3)4/h4-8,13-15,24-26H,9-12H2,1-3H3;1H3,(H,2,3,4)

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

Rescriptor; BHAP-U 90152; U-90152; BHAP U 90152; U90152; BHAP-U-90152; U 90152; DLV

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

DMSO : ≥ 40.3 mg/mL (~72.92 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.52 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 2.5 mg/mL (4.52 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

---

View More

Solubility in Formulation 3: ≥ 2.5 mg/mL (4.52 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

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