Lopinavir
Watchedfieldschanged
Verifiedrevid462093614
Pronounce/loʊˈpɪnəvɪər/
loh-PIN-ə-veer
Medlineplusa602015
DailymedidLopinavir
Routes of administrationBy mouth
Atc prefixJ05
Atc suffixAR10
Atc supplemental(with ritonavir)
Legal ukPOM
Legal usRx-only
BioavailabilityUnknown
Protein bound98-99%
MetabolismLiver
Elimination half-life5 to 6 hours
ExcretionMostly fecal
Cas number192725-17-0
Pubchem92727
DrugbankDB01601
Chemspiderid83706
Unii2494G1JF75
KeggD01425
Chembl729
SynonymsABT-378
Iupac name(2S)-N-[(2S,4S,5S)-5-[2-(2,6-dimethylphenoxy)acetamido]-4-hydroxy-1,6-diphenylhexan-2-yl]-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanamide
C37
H48
N4
O5
SmilesO=C(N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](NC(=O)[C@@H](N2C(=O)NCCC2)C(C)C)Cc3ccccc3)COc4c(cccc4C)C
Stdinchi1S/C37H48N4O5/c1-25(2)34(41-20-12-19-38-37(41)45)36(44)39-30(21-28-15-7-5-8-16-28)23-32(42)31(22-29-17-9-6-10-18-29)40-33(43)24-46-35-26(3)13-11-14-27(35)4/h5-11,13-18,25,30-32,34,42H,12,19-24H2,1-4H3,(H,38,45)(H,39,44)(H,40,43)/t30-,31-,32-,34-/m0/s1
StdinchikeyKJHKTHWMRKYKJE-SUGCFTRWSA-N

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]

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).

References

  1. ^ "FDA Approved Drug Products: Kaletra". Archived 26 January 2008 at the Wayback Machine. Retrieved 30 April 2004.
  2. ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 510. ISBN 978-3-527-60749-5.
  3. ^ Perazzolo S, Lin W, Nguyen A, Ho RJ (2021). "Systems and Clinical Pharmacology of COVID-19 Therapeutic Candidates: A Clinical and Translational Medicine Perspective". Journal of Pharmaceutical Sciences. 110 (3): 1002–1017. Bibcode:2021JPhmS.110.1002P. doi:10.1016/j.xphs.2020.11.019. PMC 7689305. PMID 33248057
  4. ^ Kaletra (lopinavir/ritonavir) capsules; (lopinavir/ritonavir) oral solution. Prescribing information. April 2009
  5. ^ Capparelli EV, Holland D, Okamoto C, Gragg B, Durelle J, Marquie-Beck J, van den Brande G, Ellis R, Letendre S (June 2005). "Lopinavir concentrations in cerebrospinal fluid exceed the 50% inhibitory concentration for HIV". AIDS. 19 (9): 949–952. doi:10.1097/01.aids.0000171409.38490.48. PMID 15905676. S2CID 3162858
  6. ^ HIV drug used to reverse effects of virus that causes cervical cancer Archived 22 March 2014 at the Wayback Machine University of Manchester, 17 February 2014.
  7. ^ Stecher C, Marinkov S, Mayr-Harting L, Katic A, Kastner MT, Rieder-Rommer FJ, Lin X, Nekhai S, Steininger C (2021). "Protein phosphatase 1 regulates Human Cytomegalovirus protein translation by restraining AMPK signaling". Frontiers in Microbiology. 12. doi:10.3389/fmicb.2021.698603. ISSN 1664-302X. PMC 8320725. PMID 34335531
  8. ^ Ammosova T, Platonov M, Ivanov A, Kont YS, Kumari N, Kehn-Hall K, Jerebtsova M, Kulkarni AA, Uren A, Kovalskyy D, Nekhai S (November 2014). "1E7-03, a low MW compound targeting host protein phosphatase-1, inhibits HIV-1 transcription". British Journal of Pharmacology. 171 (22): 5059–5075. doi:10.1111/bph.12863. PMC 4253456. PMID 25073485
  9. ^ de Wilde AH, Jochmans D, Posthuma CC, Zevenhoven-Dobbe JC, van Nieuwkoop S, Bestebroer TM, van den Hoogen BG, Neyts J, Snijder EJ (August 2014). "Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture". Antimicrobial Agents and Chemotherapy. 58 (8): 4875–4884. doi:10.1128/AAC.03011-14. PMC 4136071. PMID 24841269
  10. ^ Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, Xia J, Chen N, Xiang J, Yu T, Bai T, Xie X, Zhang L, Li C, Yuan Y, Chen H, Li H, Huang H, Tu S, Gong F, Liu Y, Wei Y, Dong C, Zhou F, Gu X, Xu J, Liu Z, Zhang Y, Li H, Shang L, Wang K, Li K, Zhou X, Dong X, Qu Z, Lu S, Hu X, Ruan S, Luo S, Wu J, Peng L, Cheng F, Pan L, Zou J, Jia C, Wang J, Liu X, Wang S, Wu X, Ge Q, He J, Zhan H, Qiu F, Guo L, Huang C, Jaki T, Hayden FG, Horby PW, Zhang D, Wang C (May 2020). "A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19". The New England Journal of Medicine. 382 (19): 1787–1799. doi:10.1056/NEJMoa2001282. PMC 7121492. PMID 32187464
  11. ^ ((Stoner, E. J.)), ((Stengel, P. J.)), ((Cooper, A. J.)) (1 March 1999). "Synthesis of ABT-378, an HIV Protease Inhibitor Candidate: Avoiding the Use of Carbodiimides in a Difficult Peptide Coupling". Organic Process Research & Development. 3 (2): 145–148. doi:10.1021/op980214p
  12. ^ ((Stoner, E. J.)), ((Cooper, A. J.)), ((Dickman, D. A.)), ((Kolaczkowski, L.)), ((Lallaman, J. E.)), ((Liu, J.-H.)), ((Oliver-Shaffer, P. A.)), ((Patel, K. M.)), ((Paterson, J. B.)), ((Plata, D. J.)), ((Riley, D. A.)), ((Sham, Hing. L.)), ((Stengel, P. J.)), ((Tien, J.-H. J.)) (1 July 2000). "Synthesis of HIV Protease Inhibitor ABT-378 (Lopinavir)". Organic Process Research & Development. 4 (4): 264–269. doi:10.1021/op990202j