Lopinavir is an antiretroviral of the protease inhibitor class. It is used against HIV infections as a fixed-dose combination with another protease inhibitor, ritonavir (lopinavir/ritonavir).
It was patented in 1995 and approved for medical use in 2000. Considered now as second-line therapy in the West, it is still prescribed in LMIC, especially among children living with HIV. Lopinavir and ritonavir can be taken as a tablet or an oral solution, a preferred option in children. In the early stages of COVID-19 pandemics, lopinavir was repurposed against the SARS-CoV-2 virus in the hope of disturbing its protease activity.
Side effects Side effects, interactions, and contraindications have only been evaluated in the drug combination lopinavir/ritonavir. They include nausea, vomiting, and stomach aches.
Pharmacology Lopinavir is highly bound to plasma proteins (98–99%).Kaletra (lopinavir/ritonavir) capsules; (lopinavir/ritonavir) oral solution. Prescribing information. April 2009
Reports are contradictory regarding lopinavir penetration into the cerebrospinal fluid (CSF). Anecdotal reports state that lopinavir cannot be detected in the CSF; however, a study of paired CSF-plasma samples from 26 patients receiving lopinavir/ritonavir found lopinavir CSF levels above the IC50 in 77% of samples.
Research A 2014 study indicates that lopinavir is effective against the human papilloma virus (HPV). The study used the equivalent of one tablet twice a day applied topically to the cervices of women with high-grade and low-grade precancerous conditions. After three months of treatment, 82.6% of the women who had high-grade disease had normal cervical conditions, confirmed by smears and biopsies.HIV drug used to reverse effects of virus that causes cervical cancer University of Manchester, 17 February 2014. Lopinavir has been shown to impair protein synthesis via AMP-activated protein kinase (AMPK) and eEF2 kinase (eEF2K) activation, a mechanism that is similar to the antiviral effect of protein phosphatase 1 inhibitors.
Lopinavir was found to inhibit MERS-CoV replication in the low-micromolar range in cell cultures. In 2020, lopinavir/ritonavir was found not to work in severe COVID-19. In this trial the medication was started typically around 13 days after the start of symptoms. Synthesis A couple of Lopinavir syntheses were reported: Below is one of them.
L-Valine [72-18-4] (1) gives N-Phenoxycarbonyl-L-valine [126147-70-4] ('2). Treatment with 3-Chloropropylamine [14753-26-5] (3) gives (S)-3-methyl-2-(2-oxotetrahydropyrimidine-1-yl)butyric acid [192725-50-1] (4). Halogenation with thionyl chloride leads to (2S)-3-Methyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)butanoyl chloride [192800-77-4] (5). Reaction with (2S,3S,5S)-5-Amino-2-dibenzylamino-1,6-diphenyl-3-hydroxyhexane, PC9890651 (6) yields (S)-N-[(2S,4S,5S)-5-(Dibenzylamino)-4-hydroxy-1,6-diphenylhexan-2-YL]-3-methyl-2-(2-oxotetrahydropyrimidin-1(2H)-YL)butanamide [192726-04-8] (7). The catalytic hydrogenation removes the protecting group to give (2S)-N-[(2S,4S,5S)-5-amino-4-hydroxy-1,6-diphenylhexan-2-yl]-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanamide [192726-05-9] (8). Amide formation with (2,6-Dimethylphenoxy)acetyl Chloride [20143-48-0] (9) completes the synthesis of lopinavir (10). References