Lopinavir
Chemical compound
From Wikipedia, the free encyclopedia
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).[1]
loh-PIN-ə-veer
| |
 | |
| Clinical data | |
|---|---|
| Pronunciation | /loʊˈpɪnəvɪər/ loh-PIN-ə-veer |
| Other names | ABT-378 |
| AHFS/Drugs.com | International Drug Names |
| MedlinePlus | a602015 |
| License data | |
| Routes of administration | By mouth |
| ATC code |
|
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | Unknown |
| Protein binding | 98-99% |
| Metabolism | Liver |
| Elimination half-life | 5 to 6 hours |
| Excretion | Mostly fecal |
| Identifiers | |
| |
| CAS Number | |
| PubChem CID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEMBL | |
| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.281.362 |
| Chemical and physical data | |
| Formula | C37H48N4O5 |
| Molar mass | 628.814 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
| (verify) | |
It was patented in 1995 and approved for medical use in 2000.[2] 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.[3]
Side effects
Side effects, interactions, and contraindications have only been evaluated in the drug combination lopinavir/ritonavir. They include nausea, vomiting, and stomach aches.[citation needed]
Pharmacology
Lopinavir is highly bound to plasma proteins (98–99%).[4]
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.[5]
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.[6] 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.[7][8]
Lopinavir was found to inhibit MERS-CoV replication in the low-micromolar range in cell cultures.[9] 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.[10]
Synthesis
A couple of Lopinavir syntheses were reported:[11][12] 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).
