scholarly journals Comparing the Greenness and Sustainability of Three Routes to an HIV Protease Inhibitor Intermediate

2021 ◽  
Author(s):  
Roger Arthur Sheldon ◽  
Moira Leanne Bode ◽  
Stephanie Gina Akakios
Keyword(s):  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Hiv Protease Inhibitor

The greenness and sustainability of three different routes for the synthesis of (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-ol (bis-furan alcohol), an advanced intermediate for a group of HIV protease inhibitors, including the FDA...

Design and synthesis of HIV protease inhibitors. Variations of the carboxyterminus of the HIV protease inhibitor L-682,679

1991 ◽  
Vol 34 (9) ◽  
pp. 2852-2857 ◽  
Author(s):  
S. Jane DeSolms ◽  
Elizabeth A. Giuliani ◽  
James P. Guare ◽  
Joseph P. Vacca ◽  
William M. Sanders ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Hiv Protease Inhibitor ◽  
Design And Synthesis

Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and therapeutic indices. PD 178390: a lead HIV protease inhibitor

1999 ◽  
Vol 7 (12) ◽  
pp. 2775-2800 ◽  
Author(s):  
J.V.N. Vara Prasad ◽  
Frederick E. Boyer ◽  
John M. Domagala ◽  
Edmund L. Ellsworth ◽  
Christopher Gajda ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Hiv Protease Inhibitor ◽  
Antiviral Activities

scholarly journals Nucleoside reverse transcriptase inhibitors prevent HIV protease inhibitor-induced atherosclerosis by ubiquitination and degradation of protein kinase C

2006 ◽  
Vol 291 (6) ◽  
pp. C1271-C1278 ◽  
Author(s):  
Emily L. Bradshaw ◽  
Xiang-An Li ◽  
Theresa Guerin ◽  
William V. Everson ◽  
Melinda E. Wilson ◽  
...  
Keyword(s):  
Side Effects ◽  
Protein Kinase ◽  
Protease Inhibitor ◽  
Reverse Transcriptase ◽  
Protease Inhibitors ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Reverse Transcriptase Inhibitors ◽  
Hiv Protease Inhibitor ◽  
Cholesterol Accumulation

HIV protease inhibitors are important pharmacological agents used in the treatment of HIV-infected patients. One of the major disadvantages of HIV protease inhibitors is that they increase several cardiovascular risk factors, including the expression of CD36 in macrophages. The expression of CD36 in macrophages promotes the accumulation of cholesterol, the development of foam cells, and ultimately atherosclerosis. Recent studies have suggested that α-tocopherol can prevent HIV protease inhibitor-induced increases in macrophage CD36 levels. Because of the potential clinical utility of using α-tocopherol to limit some of the side effects of HIV protease inhibitors, we tested the ability of α-tocopherol to prevent ritonavir, a common HIV protease inhibitor, from inducing atherosclerosis in the LDL receptor (LDLR) null mouse model. Surprisingly, α-tocopherol did not prevent ritonavir-induced atherosclerosis. However, cotreatment with the nucleoside reverse transcriptase inhibitors (NRTIs), didanosine or D4T, did prevent ritonavir-induced atherosclerosis. Using macrophages isolated from LDLR null mice, we demonstrated that the NRTIs prevented the upregulation of CD36 and cholesterol accumulation in macrophages. Treatment of LDLR null mice with NRTIs promoted the ubiquitination and downregulation of protein kinase Cα (PKC). Previous studies demonstrated that HIV protease inhibitor activation of PKC was necessary for the upregulation of CD36. Importantly, the in vivo inhibition of PKC with chelerythrine prevented ritonavir-induced upregulation of CD36, accumulation of cholesterol, and the formation of atherosclerotic lesions. These novel mechanistic studies suggest that NRTIs may provide protection from one of the negative side effects associated with HIV protease inhibitors, namely the increase in CD36 levels and subsequent cholesterol accumulation and atherogenesis.

scholarly journals Simultaneous HPLC Assay for Quantification of Indinavir, Nelfinavir, Ritonavir, and Saquinavir in Human Plasma

2000 ◽  
Vol 46 (1) ◽  
pp. 73-81 ◽  
Author(s):  
Rory P Remmel ◽  
Sagar P Kawle ◽  
Dennis Weller ◽  
Courtney V Fletcher
Keyword(s):  
Quality Control ◽  
Protease Inhibitor ◽  
Human Plasma ◽  
Protease Inhibitors ◽  
Internal Standard ◽  
Hiv Protease ◽  
Assay Method ◽  
Hiv Protease Inhibitors ◽  
Hplc Assay ◽  
Control Samples

Abstract Background: HIV protease inhibitors are recommended as part of combination antiretroviral therapy. Dual protease inhibitor therapy is also being used clinically. Consequently, a simultaneous assay for indinavir, nelfinavir, ritonavir, and saquinavir was developed. Methods: Indinavir, nelfinavir, ritonavir, and saquinavir were extracted from plasma (250 μL) with methyl-t-butyl ether at basic pH after addition of an internal standard (A-86093). The compounds were separated on a Keystone BetaBasic C4 column (250 × 3 mm i.d.) at 40 °C with a mobile phase of acetonitrile-50 mmol/L ammonium formate buffer, pH 4.1 (52:48, by volume) at a flow rate of 0.5 mL/min. Indinavir, nelfinavir, ritonavir, and the internal standard (A-86093) were detected at 218 nm, and saquinavir was detected at 235 nm. The method was validated by analysis of five triplicate analyses of calibrators along with quality-control samples at three different concentrations prepared in human plasma. Results: The extraction recovery was 87–92%. Within-run accuracy for quality-control samples was 6–8%, with CVs of 2–8%. Limits of quantification were 40–50 μg/L for indinavir, nelfinavir, and ritonavir, and 20 μg/L for saquinavir. Cross-validation with a liquid chromatography-mass spectroscopy method for saquinavir and nelfinavir was conducted with patient samples. Regression analysis revealed a good correlation (r2 >0.94) between methods. Larger variations at concentrations >4000 μg/L were observed with nelfinavir. Interference with drugs commonly used in AIDS patients was not observed. Pharmacokinetic profiles for two patients on dual protease therapy were determined. Conclusions: A reliable and rugged simultaneous HPLC assay for four HIV protease inhibitors was developed. The assay method is convenient for clinical laboratories involved in therapeutic drug monitoring for HIV protease inhibitors. The assay has enough sensitivity to conduct pharmacokinetic studies in patients taking more than one HIV protease inhibitor along with other antiretroviral medications.

scholarly journals The HIV protease inhibitor, ritonavir, corrects diverse brain phenotypes across development in mouse model of DYT-TOR1A dystonia

2021 ◽  
Vol 13 (607) ◽  
pp. eabd3904
Author(s):  
Zachary F. Caffall ◽  
Bradley J. Wilkes ◽  
Ricardo Hernández-Martinez ◽  
Joseph E. Rittiner ◽  
Jennifer T. Fox ◽  
...  
Keyword(s):  
Mouse Model ◽  
Protease Inhibitor ◽  
Diffusion Tensor ◽  
Hiv Protease ◽  
Drug Candidate ◽  
Hiv Protease Inhibitors ◽  
Hiv Protease Inhibitor ◽  
Protein Variant ◽  
Oral Medications ◽  
Disease Modifying

Dystonias are a group of chronic movement–disabling disorders for which highly effective oral medications or disease-modifying therapies are lacking. The most effective treatments require invasive procedures such as deep brain stimulation. In this study, we used a high-throughput assay based on a monogenic form of dystonia, DYT1 (DYT-TOR1A), to screen a library of compounds approved for use in humans, the NCATS Pharmaceutical Collection (NPC; 2816 compounds), and identify drugs able to correct mislocalization of the disease-causing protein variant, ∆E302/3 hTorsinA. The HIV protease inhibitor, ritonavir, was among 18 compounds found to normalize hTorsinA mislocalization. Using a DYT1 knock-in mouse model to test efficacy on brain pathologies, we found that ritonavir restored multiple brain abnormalities across development. Ritonavir acutely corrected striatal cholinergic interneuron physiology in the mature brain and yielded sustained correction of diffusion tensor magnetic resonance imaging signals when delivered during a discrete early developmental window. Mechanistically, we found that, across the family of HIV protease inhibitors, efficacy correlated with integrated stress response activation. These preclinical results identify ritonavir as a drug candidate for dystonia with disease-modifying potential.

scholarly journals Applications of Click Chemistry in the Development of HIV Protease Inhibitors

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Mukesh M. Mudgal ◽  
Nagaraju Birudukota ◽  
Mayur A. Doke
Keyword(s):  
Protease Inhibitor ◽  
Click Chemistry ◽  
Protease Inhibitors ◽  
Highly Active Antiretroviral Therapy ◽  
Click Reaction ◽  
Large Body ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Infected People ◽  
Hiv 1

Acquired Immunodeficiency Syndrome (AIDS) has been devastating for millions of people around the world. Inhibition of the human immunodeficiency virus (HIV) protease is among the most important approaches for the therapeutic intervention in HIV infection. Since the discovery of the HIV-1 protease, this enzyme has been considered as a key target for the inhibition of viral replication. A large body of research has been done to develop an effective HIV-1 protease inhibitor. There are to date 10 HIV-1 protease inhibitor drugs approved by the Food and Drug Administration (FDA) that have improved the survival and quality of life of HIV infected people. These drugs are prescribed in combination with the reverse transcriptase inhibitors, which is referred to as highly active antiretroviral therapy (HAART). The HIV-1 protease inhibitors play a vital role in HAART. The applications of click chemistry are dispersing in the field of drug discovery. Recently, click chemistry has captured a lot of attention and has become a powerful tool for the synthesis of medicinal skeletons in the discovery of anti-HIV drugs. Click reaction is a well-known method for making carbon−heteroatom−carbon bonds. Click reactions are popular because they are wide in scope, of high yielding, quick to perform, and easy to purify. In this review, we outlined current approaches towards the development of HIV-1 protease inhibitors employing click chemistry.

HIV protease inhibitors protect apolipoprotein B from degradation by the proteasome: A potential mechanism for protease inhibitor-induced hyperlipidemia

2001 ◽  
Vol 7 (12) ◽  
pp. 1327-1331 ◽  
Author(s):  
Jun-Shan Liang ◽  
Oliver Distler ◽  
David A. Cooper ◽  
Haris Jamil ◽  
Richard J. Deckelbaum ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Apolipoprotein B ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Potential Mechanism

Altered Myocellular and Abdominal Fat Partitioning Predict Disturbance in Insulin Action in HIV Protease Inhibitor-Related Lipodystrophy

Diabetes ◽  
2002 ◽  
Vol 51 (11) ◽  
pp. 3163-3169 ◽  
Author(s):  
S. K. Gan ◽  
K. Samaras ◽  
C. H. Thompson ◽  
E. W. Kraegen ◽  
A. Carr ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Insulin Action ◽  
Abdominal Fat ◽  
Hiv Protease ◽  
Hiv Protease Inhibitor
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