Nelfinavir undergoes oxidative metabolism in the liver primarily by CYP3A4, but also by CYP2C19 and CYP2D6. Its major hydroxy-t-butylamide metabolite (M8) has in vitro antiretroviral activity comparable to that of the parent drug but achieves plasma levels that are only 40% of nelfinavir levels. The M8 metabolite is generated primarily by CYP2C19.
Exploiting protein homeostasis is a new therapeutic approach in cancer. Nelfinavir (NFV) is an HIV protease inhibitor that induces endoplasmic reticulum (ER) stress in cancer cells. Under conditions of ER stress, misfolded proteins are transported from the ER back to the cytosol for subsequent degradation by the ubiquitin-proteasome system. Bortezomib (BZ) is a proteasome inhibitor and interferes with degradation of misfolded proteins. Here, we show that NFV and BZ enhance proteotoxicity in non-small cell lung cancer (NSCLC) and multiple myeloma (MM) cells. The combination synergistically inhibited cell proliferation and induced cell death. Activating transcription factor (ATF)3 and CCAAT-enhancer binding protein homologous protein (CHOP), markers of ER stress, were rapidly increased, and their siRNA-mediated knockdown inhibited cell death. Knockdown of double-stranded RNA activated protein kinase-like ER kinase, a signal transducer in ER stress, significantly decreased apoptosis. Pretreatment with the protein synthesis inhibitor, cycloheximide, decreased levels of ubiquitinated proteins, ATF3, CHOP, and the overall total cell death, suggesting that inhibition of protein synthesis increases cell survival by relieving proteotoxic stress. The NFV/BZ combination inhibited the growth of NSCLC xenografts, which correlated with the induction of markers of ER stress and apoptosis. Collectively, these data show that NFV and BZ enhance proteotoxicity in NSCLC and MM cells, and suggest that this combination could tip the precarious balance of protein homeostasis in cancer cells for therapeutic gain.
Competition for the cytochrome p450 enzyme CYP3A by nelfinavir may inhibit the metabolism of these medications /amiodarone, astemizole, cisapride, ergot derivatives, midazolam, quinidine, terfenadine, triazolam/ and create the potential for serious and/or life threatening cardiac arrhythmias or prolonged sedation; concurrent use is not recommended.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
相互作用
与拉米夫丁同时使用会导致拉米夫丁的AUC增加10%。
Concurrent use /with lamivudine/ causes a 10% increase in the AUC of lamivudine.
Concurrent administration /of oral contraceptives such as: ethinyl estradiol or norethindrone/ with nelfinavir causes a decrease in the plasma concentrations of these medications; alternate or additional contraceptive measures should be used.
Treatment of overdose: To decrease absorption: Patients may benefit from treatment with activated charcoal. Monitoring: Patient's vital signs should be monitored. Supportive care: Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.
Distribution of nelfinavir into body tissues and fluids has not been fully characterized. The volume of distribution of nelfinavir following oral administration in animals is 27 L/kg, suggesting extensive tissue distribution. Studies in rats indicate that, at 4 hours after oral administration of radiolabeled nelfinavir, concentrations of the drug in liver, lymph nodes, pancreas, kidney, lungs, submaxillary glands, heart, and spleen exceed concurrent plasma concentrations. Nelfinavir has been detected in brain tissue in rats.
Nelfinavir is greater than 98% bound to plasma proteins, mostly to albumin and alpha1-acid glycoprotein. It is present in the CSF at less than 1% of plasma concentrations, at least in part due to its extensive binding to plasma protein but perhaps also due to the P-glycoprotein at the blood-brain barrier.
Nelfinavir and its metabolites are eliminated primarily in feces, with less than 2% of the drug being excreted in the urine. Moderate or severe liver disease may prolong the half-life and increase plasma concentrations of the parent drug while lowering plasma concentrations of M8 /(a major hydroxy-t-butylamide metabolite)/.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
奈非那韦的吸收对食物的影响非常敏感；中等脂肪餐会使AUC增加2到3倍，高脂肪餐则会达到更高的浓度。
Nelfinavir absorption is very sensitive to food effects; a moderate fat meal increases the AUC 2 to 3 fold, and higher concentrations are achieved with high fat meals.
Optimization of an Electrolyte System for the Simultaneous Separation of Nelfinavir Mesylate and Two Impurities by Micellar Electrokinetic Chromatography
摘要：
A methodology for the simultaneous determination of nelfinavir mesylate and the impurities 3-hydroxy-2-methylbenzoic acid and (2R,3R)-4-((3S,4aS,8aS)-3-(tert-butylcarbamoyl) octahydroisoquinolin-2(1H)-yl)-3-hydroxy-1-(phenylthio)butan-2-aminium benzoate by micellar electrokinetic chromatography, with an analysis time of 25 min, was proposed. An electrolyte composed of sodium tetraborate buffer (pH 9.24; 25 mmol L-1), sodium dodecyl sulphate (9 mmol L-1) and methanol (10%, v/v) was optimized using a mixed-level factorial design, with direct detection at 200 nm. After evaluating some figures of merit, such as selectivity, linearity, precision, limit of detection, limit of quantification, accuracy and robustness (using Youden's test), the method was successfully applied to the analysis of nelfinavir mesylate and its impurities in a pharmaceutical formulation. The optimized methodology is demonstrated to be useful in the determination of these analytes in a synthesis monitoring process, in raw materials and in pharmaceutical formulations, while offering low solvent consumption, requiring a small sample and using non-specific columns as advantages.
[EN] SPIROCYCLIC HETEROCYCLE COMPOUNDS USEFUL AS HIV INTEGRASE INHIBITORS<br/>[FR] COMPOSÉS HÉTÉROCYCLIQUES SPIROCYCLIQUES UTILES COMME INHIBITEURS DU VIH
申请人：MERCK SHARP & DOHME
公开号：WO2016094198A1
公开（公告）日：2016-06-16
The present invention relates to Spirocyclic Heterocycle Compounds of Formula (I): (I) and pharmaceutically acceptable salts thereof, wherein A, B, X, R1, R2, R3 and R4 are as defined herein. The present invention also relates to compositions comprising at least one Spirocyclic Heterocycle Compound, and methods of using the Spirocyclic Heterocycle Compounds for treating or preventing HIV infection in a subject.
The present invention provides compounds, compositions thereof, and methods of using the same.
本发明提供了化合物、其组合物以及使用这些化合物的方法。
[EN] ANTIBODY-DRUG CONJUGATES AND THERAPEUTIC METHODS USING THE SAME<br/>[FR] CONJUGUÉS ANTICORPS-MÉDICAMENT ET PROCÉDÉS THÉRAPEUTIQUES UTILISANT CEUX-CI
申请人：GLAXOSMITHKLINE INTELLECTUAL PROPERTY (NO 2) LTD
公开号：WO2018002902A1
公开（公告）日：2018-01-04
The invention discloses an antibody-drug conjugate of Formula (I): (I) Ab-[L-Dn]x wherein: Ab comprises a broadly neutralizing anti-HIV antibody; L comprises a linker molecule covalently bonded to said broadly neutralizing anti-HIV antibody; D comprises one or more drugs comprising an HIV therapeutic compound covalently bonded to said linker molecule L, wherein said one or more broadly neutralizing anti-HIV antibodies Ab specifically bind to an HIV envelope glycoprotein and said one or more drugs D specifically bind to an HIV envelope glycoprotein; n is selected from 1-4; and x is selected from 1-12.
[EN] AMINE-LINKED C3-GLUTARIMIDE DEGRONIMERS FOR TARGET PROTEIN DEGRADATION<br/>[FR] DÉGRONIMÈRES DE C3-GLUTARIMIDE LIÉS À UNE AMINE POUR LA DÉGRADATION DE PROTÉINES CIBLES
申请人：C4 THERAPEUTICS INC
公开号：WO2017197051A1
公开（公告）日：2017-11-16
This invention provides amine-linked C3-glutarimide Degronimers and Degrons for therapeutic applications as described further herein, and methods of use and compositions thereof as well as methods for their preparation.
[EN] PYRIDINE CARBOXAMIDE AND METHODS FOR INHIBITING HIV INTEGRASE<br/>[FR] CARBOXAMIDE DE PYRIDINE ET METHODES PERMETTANT D'INHIBER L'INTEGRASE DU VIH
申请人：VIROCHEM PHARMA INC
公开号：WO2005042524A1
公开（公告）日：2005-05-12
Compounds of formula (I): wherein R1, R2, R4, R10, R11, and Q are as defined herein, and their pharmaceutically acceptable salts, are useful in the prevention or treatment of HIV infections.
