Multiple myeloma cell growth is inhibited by nelfinavir (AG1341) (1-10 μM; 48) [4]. Fresh nelfinavir (1-10 μM; 17 hours) causes inflammation in multiple myeloma cell lines and inhibits 26S chymotrypsin amyloid chromosomal activity, damages ischemia, and causes cellular burst in myeloma cell lines [4]. [4] Nelfinavir (5 μM; 0–24 hours) decreases AKT phosphorylation. Anise dye increases caspase-3 stability, decreases ERK1/2, AKT, and STAT-3 phosphorylation, and activates the unfolded protein response system [4]. Another SARS-CoV 3CL pro adaptor with an IC50 of 35.93 μM is nelfinavir.

In NOD/SCID mice, nelfinavir (AG1341) (75 mg/kg; i.p.; 5 days per week for 21 days) inhibits the proliferation of multiple myeloma cells [4].

Cell proliferation assay [4]
Cell Types: RPMI, LP1, U266, OPM2 and MM1S Cell
Tested Concentrations: 1, 2, 5, 10 μM
Incubation Duration: 48 hrs (hours)
Experimental Results: Inhibition of RPMI , LP1, U266, proliferation. OPM2 and MM1S cell lines were dose-dependent, with IC50 of 1-5 μM.

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Apoptosis analysis [4]
Cell Types: LP1 and U266 Cell
Tested Concentrations: 1-10 μM
Incubation Duration: 17 hrs (hours)
Experimental Results: A dose-dependent increase in the percentage of Annexin V+/propidium iodide+ cells was induced.

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Western Blot Analysis [4]
Cell Types: U266 cells
Tested Concentrations: 5 μM
Incubation Duration: 0-24 hrs (hours)
Experimental Results: AKT phosphorylation level diminished in U266 cells.

Animal/Disease Models: NOD/SCID (severe combined immunodeficient) mouse (carrying U266-luc cells) [4]
Doses: 75 mg/kg
Route of Administration: intraperitoneal (ip) injection; 5 days a week for 21 days
Experimental Results: MM cells in NOD/SCID (severe combined immunodeficient) mouse diminished growth.

Absorption, Distribution and Excretion
Well absorbed following oral administration.
The majority (87%) of an oral 750 mg dose containing 14C-nelfinavir was recovered in the feces; fecal radioactivity consisted of numerous oxidative metabolites (78%) and unchanged nelfinavir (22%). Only 1–2% of the dose was recovered in urine, of which unchanged nelfinavir was the major component.
The apparent volume of distribution following oral administration of nelfinavir was 2-7 L/kg.
Oral clearance estimates after single doses (24-33 L/h) and multiple doses (26-61 L/h) indicate that nelfinavir is a drug with medium to high hepatic bioavailability.

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Metabolism / Metabolites
Unchanged nelfinavir comprised 82-86% of the total plasma radioactivity after a single oral 750 mg dose of 14C-nelfinavir. In vitro, multiple cytochrome P-450 enzymes including CYP3A and CYP2C19 are responsible for the metabolism of nelfinavir. One major and several minor oxidative metabolites were found in plasma. The major oxidative metabolite has in vitro antiviral activity comparable to the parent drug.
Nelfinavir has known human metabolites that include 3,4-Dihydroxynelfinavir and Nelfinavir hydroxyl-t- butylamide.

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Biological Half-Life
The terminal half-life in plasma was typically 3.5 to 5 hours.

Hepatotoxicity
Some degree of serum aminotransferase elevation occurs in a high proportion of patients taking nelfinavir containing antiretroviral regimens. Moderate-to severe elevations in serum aminotransferase levels (>5 times the upper limit of normal) are found in only 3% to 10% of patients, although rates may be higher in patients with HIV-HCV coinfection. These elevations are usually asymptomatic and self-limited and can resolve even with continuation of the medication. Clinically apparent acute liver injury due to nelfinavir is rare. The few cases that have been reported have arisen after 1 to 8 weeks of starting nelfinavir, and the pattern of serum enzyme elevations has not been reported, but is likely to have been hepatocellular (Case 1). Signs of hypersensitivity (fever, rash, eosinophilia) can occur as can autoantibody formation but these features are not very prominent. The acute liver injury due to nelfinavir is usually self-limited, but it can be severe, and isolated cases of acute liver failure have been reported to the sponsor, although not in great detail. In HBV or HCV coinfected patients, some instances appear to be due to exacerbation of the underlying chronic liver disease, perhaps as a result of sudden immune reconstitution. Nelfinavir therapy has not been clearly linked to lactic acidosis and acute fatty liver that is reported in association with several nucleoside analogue reverse transcriptase inhibitors used to treat HIV infection.
Likelihood score: D (possible rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Nelfinavir levels in milk are low and the drug is usually not detectable in the serum of breastfed infants. However, some evidence of nelfinavir-induced adverse reactions in breastfed infants exists. Nelfinavir is not a recommended agent during breastfeeding. Achieving and maintaining viral suppression with antiretroviral therapy decreases breastfeeding transmission risk to less than 1%, but not zero. Individuals with HIV who are on antiretroviral therapy with a sustained undetectable viral load and who choose to breastfeed should be supported in this decision. If a viral load is not suppressed, banked pasteurized donor milk or formula is recommended.
◉ Effects in Breastfed Infants
A study compared the frequency of rash, hepatotoxicity, and hyperbilirubinemia among 464 breastfed infants whose mothers were taking either nelfinavir (n = 206) or nevirapine (n = 258) along with zidovudine and lamivudine for HIV infection during pregnancy and postpartum. Infants were examined during the first, second and sixth weeks postpartum. Moderate rash occurred in 7 (2.7%) of the infant exposed to nevirapine and one (0.5%) infant exposed to nelfinavir. Rash occurred at a median of 2 weeks postpartum. Four infants (1.9%) exposed to nelfinavir developed hepatotoxicity (3 moderate and 1 severe) and none exposed to nevirapine. Twenty-one infants (4.5%) developed high-risk hyperbilirubinemia, all prior to 48 hours of age, but there was no difference in exposure between the two drugs.
◉ Effects on Lactation and Breastmilk
Gynecomastia has been reported among men receiving highly active antiretroviral therapy. Gynecomastia is unilateral initially, but progresses to bilateral in about half of cases. No alterations in serum prolactin were noted and spontaneous resolution usually occurred within one year, even with continuation of the regimen. Some case reports and in vitro studies have suggested that protease inhibitors might cause hyperprolactinemia and galactorrhea in some male patients, although this has been disputed. The relevance of these findings to nursing mothers is not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

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Protein Binding
Nelfinavir in serum is extensively protein-bound (>98%).

[1]. Nelfinavir suppresses signaling and nitric oxide production by human aortic endothelial cells: protective effects of thiazolidinediones. Ochsner J. 2013 Spring;13(1):76-90.

[2]. Nelfinavir, A lead HIV protease inhibitor, is a broad-spectrum, anticancer agent that inducesendoplasmic reticulum stress, autophagy, and apoptosis in vitro and in vivo. Clin Cancer Res. 2007 Sep 1;13(17):5183-94.

[3]. Nelfinavir mesylate (AG1343): a potent, orally bioavailable inhibitor of HIV-1 protease. J Med Chem. 1997 Nov 21;40(24):3979-85.

[4]. The human immunodeficiency virus-1 protease inhibitor nelfinavir impairs proteasome activity and inhibits the proliferation of multiple myeloma cells in vitro and in vivo. Haematologica. 2012;97(7):1101‐1109.

[5]. Bardoxolone and bardoxolone methyl, two Nrf2 activators in clinical trials, inhibit SARS-CoV-2 replication and its 3C-like protease. Signal Transduct Target Ther. 2021 May 29;6(1):212.

Nelfinavir is an aryl sulfide that is used (as its mesylate salt) for treatment of HIV and also exhibits some anticancer properties. It has a role as a HIV protease inhibitor and an antineoplastic agent. It is a member of benzamides, a member of phenols, an aryl sulfide, a secondary alcohol, a tertiary amino compound and an organic heterobicyclic compound. It is a conjugate base of a nelfinavir(1+).
Nelfinavir is a potent HIV-1 protease inhibitor. It is used in combination with other antiviral drugs in the treatment of HIV in both adults and children. Nelfinavir inhibits the HIV viral proteinase enzyme which prevents cleavage of the gag-pol polyprotein, resulting in noninfectious, immature viral particles.
Nelfinavir is a Protease Inhibitor. The mechanism of action of nelfinavir is as a HIV Protease Inhibitor, and Cytochrome P450 3A Inhibitor.
Nelfinavir is an antiretroviral protease inhibitor used in the therapy and prevention of human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS). Nelfinavir can cause transient and usually asymptomatic elevations in serum aminotransferase levels and is a rare cause of clinically apparent, acute liver injury. In HBV or HCV coinfected patients, hepatic injury during antiretroviral therapy that includes nelfinavir may be a result of exacerbation of the underlying chronic hepatitis B or C, rather than a direct effect of the medication.
Nelfinavir is a synthetic antiviral agent that selectively binds to and inhibits human immunodeficiency virus (HIV) protease. Nelfinavir has activity against HIV 1 and 2.
A potent HIV protease inhibitor. It is used in combination with other antiviral drugs in the treatment of HIV in both adults and children.
See also: Nelfinavir Mesylate (has salt form).

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Drug Indication
Used in combination with other antiviral drugs in the treatment of HIV in both adults and children.
FDA Label
Viracept is indicated in antiretroviral combination treatment of human-immunodeficiency-virus (HIV-1)-infected adults, adolescents and children of three years of age and older. In protease-inhibitor (PI)-experienced patients, the choice of nelfinavir should be based on individual viral resistance testing and treatment history.

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Mechanism of Action
HIV viral protease is an important enzyme for HIV maturation and pathogenicity since HIV produces its structural and key proteins in the form of a polyprotein that needs to be cleaved by a protease. HIV protease is synthesized as part of the Gag-pol polyprotein, where Gag encodes for the capsid and matrix protein to form the outer protein shell, and Pol encodes for the reverse transcriptase and integrase protein to synthesize and incorporate its genome into host cells. The Gag-pol polyprotein undergoes proteolytic cleavage by HIV protease to produce 66 molecular species which will assume conformational changes to become fully active. Inhibition of protease, therefore, prevents HIV virion from fully maturing and becoming infective. Nelfinavir is a competitive inhibitor of the HIV protease by reversibly binding to the active site of the enzyme, preventing it from interacting with its substrate to produce mature and infectious viral particles.

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Pharmacodynamics
Nelfinavir is a protease inhibitor with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Protease inhibitors block the part of HIV called protease. HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Nelfinavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs.

C32H45N3O4S

567.789

567.3131

C, 67.69; H, 7.99; N, 7.40; O, 11.27; S, 5.65

159989-64-7

Nelfinavir Mesylate;159989-65-8;Nelfinavir-d3;1217629-70-3

64143

White to off-white solid powder

1.22g/cm3

786.8ºC at 760 mmHg

429.7ºC

4.38E-26mmHg at 25°C

1.618

6.052

4

6

10

40

830

5

S(C1C([H])=C([H])C([H])=C([H])C=1[H])C([H])([H])[C@@]([H])([C@@]([H])(C([H])([H])N1[C@]([H])(C(N([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])=O)C([H])([H])[C@]2([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[C@]2([H])C1([H])[H])O[H])N([H])C(C1C([H])=C([H])C([H])=C(C=1C([H])([H])[H])O[H])=O

QAGYKUNXZHXKMR-HKWSIXNMSA-N

InChI=1S/C32H45N3O4S/c1-21-25(15-10-16-28(21)36)30(38)33-26(20-40-24-13-6-5-7-14-24)29(37)19-35-18-23-12-9-8-11-22(23)17-27(35)31(39)34-32(2,3)4/h5-7,10,13-16,22-23,26-27,29,36-37H,8-9,11-12,17-20H2,1-4H3,(H,33,38)(H,34,39)/t22-,23+,26-,27-,29+/m0/s1

(3S,4aS,8aS)-N-tert-butyl-2-[(2R,3R)-2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl)amino]-4-phenylsulfanylbutyl]-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-3-carboxamide

Nelfinavir free base; AG-1343; AG 1343; AG1343; Nelfinavir; Viracept.

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)

DMSO : ≥ 100 mg/mL (176.12 mM

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.40 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.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.40 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.

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Solubility in Formulation 3: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (4.40 mM)

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