Cobicistat

Last updated

Cobicistat
Cobicistat structure.svg
Clinical data
Pronunciation /koʊˈbɪsɪstæt/
koh-BIS-i-stat
Trade names Tybost
Other namesGS-9350
AHFS/Drugs.com Monograph
MedlinePlus a616029
License data
ATC code
Legal status
Legal status
Identifiers
  • 1,3-thiazol-5-ylmethyl [(2R,5R)-5-{[(2S)-2-[(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)amino]-4-(morpholin-4-yl)butanoyl]amino}-1,6-diphenylhexan-2-yl]carbamate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C40H53N7O5S2
Molar mass 776.03 g·mol−1
3D model (JSmol)
  • CC(C)c1nc(cs1)CN(C)C(=O)NC(CCN2CCOCC2)C(=O)NC(CCC(Cc3ccccc3)NC(=O)OCc4cncs4)Cc5ccccc5
  • InChI=1S/C40H53N7O5S2/c1-29(2)38-43-34(27-53-38)25-46(3)39(49)45-36(16-17-47-18-20-51-21-19-47)37(48)42-32(22-30-10-6-4-7-11-30)14-15-33(23-31-12-8-5-9-13-31)44-40(50)52-26-35-24-41-28-54-35/h4-13,24,27-29,32-33,36H,14-23,25-26H2,1-3H3,(H,42,48)(H,44,50)(H,45,49)/t32-,33-,36+/m1/s1 Yes check.svgY
  • Key:ZCIGNRJZKPOIKD-CQXVEOKZSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Cobicistat, sold under the brand name Tybost, is a medication for use in the treatment of human immunodeficiency virus infection (HIV/AIDS). Its major mechanism of action is through the inhibition of human CYP3A proteins. [1] [ non-primary source needed ]

Contents

Like ritonavir (Norvir), cobicistat is of interest for its ability to inhibit liver enzymes that metabolize other medications used to treat HIV, notably elvitegravir, an HIV integrase inhibitor. By combining cobicistat with elvitegravir, higher concentrations of the latter are achieved in the body with lower dosing, theoretically enhancing elvitegravir's viral suppression while diminishing its adverse side-effects. In contrast with ritonavir, the only other booster approved for use as a part of HAART, cobicistat has no anti-HIV activity of its own. [2]

Cobicistat is a component of three four-drug, fixed-dose combination HIV treatments. The first, elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil, is marketed as Stribild and was approved by the FDA in August 2012 for use in the United States. [2] [3] The second, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, is marketed as Genvoya and was approved by the FDA in November 2015 for use in the United States. Both Stribild and Genvoya are owned by Gilead Sciences. The third, cobicistat/darunavir/emtricitabine/tenofovir alafenamide, is marketed as Symtuza and was FDA approved July 17, 2018 and is owned by Janssen Pharmaceuticals. [4]

Additionally, there is a fixed-dose combination of cobicistat and the protease inhibitor darunavir (darunavir/cobicistat; marketed as Prezcobix by Janssen Therapeutics), and a fixed-dose combination of cobicistat and protease inhibitor atazanavir (atazanavir/cobicistat; marketed as Evotaz by Bristol-Myers Squibb). Both Prezcobix and Evotaz were approved by the FDA in January 2015.

Cobicistat is a potent inhibitor of cytochrome P450 3A enzymes, including the important CYP3A4 subtype. It also inhibits intestinal transport proteins, increasing the overall absorption of several HIV medications, including atazanavir, darunavir, and tenofovir alafenamide. [5]

Chemistry

Cobicistat is a drug analogue of ritonavir, in which the valine moiety is exchanged for a 2-morpholinoethyl group, and the backbone hydroxyl group is removed. These changes effectively eliminate the anti-HIV activity of ritonavir while preserving its inhibitory effects on the CYP3A isozyme family of proteins. [6] Cobicistat is therefore able to increase plasma concentration of other coadministered anti-HIV drugs without the risk of causing cobicistat-resistant mutations in the HIV virus.

Synthesis

Cobicistat may be synthesized from any number of commercially available starting materials. The synthesis shown below utilizes L-methionine and bromoacetic acid as starting materials. [7]

Discovery and development

Cobicistat was developed through structure-activity relationship studies using ritonavir and desoxyritonavir as lead compounds. These studies were conducted by scientists at Gilead Sciences, and successfully optimized ritonavir into a potent CYP3A inhibitor lacking anti-HIV activity. Cobicistat shows potent, selective inhibition of the CYP3A isozyme family (IC50 0.15 μM) compared to some CYP1A and CYP2C isozymes. [8] As cobicistat was discovered using structure-activity relationship studies, its CYP3A binding is still poorly understood; however, research on the protein-ligand interactions between CYP3A4 and ritonavir analogues [9] demonstrates that CYP 3A4 residues Ile369, Ala370, Met371, as well as Arg105 and Ser119, play an important role in ritonavir analogue inhibition of CYP3A4. [10] [11]

Related Research Articles

<span class="mw-page-title-main">Emtricitabine</span> Antiretroviral drug used to treat HIV infection

Emtricitabine, with trade name Emtriva, is a nucleoside reverse-transcriptase inhibitor (NRTI) for the prevention and treatment of HIV infection in adults and children. In 2019, it was the 494th most commonly prescribed medication in the United States, with more than 3 thousand prescriptions.

ATC code J05Antivirals for systemic use is a therapeutic subgroup of the Anatomical Therapeutic Chemical Classification System, a system of alphanumeric codes developed by the World Health Organization (WHO) for the classification of drugs and other medical products. Subgroup J05 is part of the anatomical group J Antiinfectives for systemic use.

<span class="mw-page-title-main">Ritonavir</span> Antiretroviral medication

Ritonavir, sold under the brand name Norvir, is an antiretroviral medication used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhibitor, though it now mainly serves to boost the potency of other protease inhibitors. It may also be used in combination with other medications to treat hepatitis C and COVID-19. It is taken by mouth.

<span class="mw-page-title-main">Tenofovir disoproxil</span> Antiviral drug used to treat or prevent HIV and hepatitis infections

Tenofovir disoproxil, sold under the brand name Viread among others, is a medication used to treat chronic hepatitis B and to prevent and treat HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention of HIV/AIDS among those at high risk before exposure, and after a needlestick injury or other potential exposure. It is sold both by itself and together in combinations such as emtricitabine/tenofovir, efavirenz/emtricitabine/tenofovir, and elvitegravir/cobicistat/emtricitabine/tenofovir. It does not cure HIV/AIDS or hepatitis B. It is available by mouth as a tablet or powder.

<span class="mw-page-title-main">Saquinavir</span> Chemical compound

Saquinavir, sold under the brand name Invirase among others, is an antiretroviral medication used together with other medications to treat or prevent HIV/AIDS. Typically it is used with ritonavir or lopinavir/ritonavir to increase its effect. It is taken by mouth.

Synergistic enhancers of antiretrovirals usually do not possess any antiretroviral properties alone, but when they are taken concurrently with antiretroviral drugs they enhance the effect of that drug.

<span class="mw-page-title-main">Darunavir</span> Antiretroviral medication

Darunavir (DRV), sold under the brand name Prezista among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. It is generally recommended for use with other antiretrovirals. It is often used with low doses of ritonavir or cobicistat to increase darunavir levels. It may be used for prevention after a needlestick injury or other potential exposure. It is taken by mouth once to twice a day.

Integrase inhibitors (INIs) are a class of antiretroviral drug designed to block the action of integrase, a viral enzyme that inserts the viral genome into the DNA of the host cell. Since integration is a vital step in retroviral replication, blocking it can halt further spread of the virus. Integrase inhibitors were initially developed for the treatment of HIV infection, but have been applied to other retroviruses. The class of integrase inhibitors called integrase strand transfer inhibitors (INSTIs) are in established medical use. Other classes, such as allosteric integrase inhibitors (ALLINIs) or integrase binding inhibitors (INBIs), are still experimental.

<span class="mw-page-title-main">Bergamottin</span> Chemical compound

Bergamottin (5-geranoxypsoralen) is a natural furanocoumarin found in the pulp of pomelos and grapefruits. It is also found in the peel and pulp of the bergamot orange, from which it was first isolated and from which its name is derived.

<span class="mw-page-title-main">Elvitegravir</span> Chemical compound

Elvitegravir (EVG) is an integrase inhibitor used to treat HIV infection. It was developed by the pharmaceutical company Gilead Sciences, which licensed EVG from Japan Tobacco in March 2008. The drug gained approval by the U.S. Food and Drug Administration on August 27, 2012, for use in adult patients starting HIV treatment for the first time as part of the fixed dose combination known as Stribild. On September 24, 2014, the FDA approved Elvitegravir as a single pill formulation under the trade name Vitekta. On November 5, 2015, the FDA approved the drug for use in patients affected with HIV-1 as a part of a second fixed dose combination pill known as Genvoya.

<span class="mw-page-title-main">Rilpivirine</span> HIV treatment

Rilpivirine, sold under the brand names Edurant and Rekambys, is a medication, developed by Tibotec, used for the treatment of HIV/AIDS. It is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with higher potency, longer half-life and reduced side-effect profile compared with older NNRTIs such as efavirenz.

Many major physiological processes depend on regulation of proteolytic enzyme activity and there can be dramatic consequences when equilibrium between an enzyme and its substrates is disturbed. In this prospective, the discovery of small-molecule ligands, like protease inhibitors, that can modulate catalytic activities has an enormous therapeutic effect. Hence, inhibition of the HIV protease is one of the most important approaches for the therapeutic intervention in HIV infection and their development is regarded as major success of structure-based drug design. They are highly effective against HIV and have, since the 1990s, been a key component of anti-retroviral therapies for HIV/AIDS.

<span class="mw-page-title-main">Lopinavir/ritonavir</span> Combination medication for HIV/AIDS

Lopinavir/ritonavir (LPV/r), sold under the brand name Kaletra among others, is a fixed-dose combination antiretroviral medication for the treatment and prevention of HIV/AIDS. It combines lopinavir with a low dose of ritonavir. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlestick injury or other potential exposure. It is taken by mouth as a tablet, capsule, or solution.

<span class="mw-page-title-main">Daniel Berger (physician)</span> American physician

Daniel Berger is a leading HIV specialist in the United States. A clinical associate professor at the Chicago campus of the University of Illinois College of Medicine, Berger is also founder and medical director of Northstar Medical Center, Chicago's largest private HIV/AIDS research and treatment center.

<span class="mw-page-title-main">Tenofovir alafenamide</span> Chemical compound

Tenofovir alafenamide, sold under the brand name Vemlidy, is an antiviral medication used against hepatitis B and HIV. It is used for the treatment of chronic hepatitis B virus (HBV) infection in adults with compensated liver disease and is given in combination with other medications for the prevention and treatment of HIV. It is taken by mouth.

Elvitegravir/cobicistat/emtricitabine/tenofovir, sold under the brand name Stribild, also known as the Quadpill, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. Elvitegravir, emtricitabine and tenofovir disoproxil directly suppress viral reproduction. Cobicistat increases the effectiveness of the combination by inhibiting the liver and gut wall enzymes that metabolize elvitegravir. It is taken by mouth. It is manufactured by Gilead Sciences.

<span class="mw-page-title-main">Bictegravir</span> Chemical compound

Bictegravir is a second-generation integrase inhibitor (INSTI) class that was structurally derived from an earlier compound dolutegravir by scientists at Gilead Sciences. In vitro and clinical results were presented by Gilead in the summer of 2016. In 2016, bictegravir was in a Phase 3 trial as part of a single tablet regimen in combination with tenofovir alafenamide (TAF) and emtricitabine (FTC) for the treatment of HIV-1 infection.

<span class="mw-page-title-main">Bictegravir/emtricitabine/tenofovir alafenamide</span> Fixed dose combination HIV drug

Bictegravir/emtricitabine/tenofovir alafenamide, sold under the brand name Biktarvy, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. It contains bictegravir, a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor; emtricitabine, an HIV-1 nucleoside analog reverse transcriptase inhibitor; and tenofovir alafenamide, an HIV-1 nucleoside analog reverse transcriptase inhibitor.

Atazanavir/cobicistat, sold under the brand name Evotaz, is a fixed-dose combination antiretroviral medication used to treat and prevent HIV/AIDS. It contains atazanavir and cobicistat. Atazanavir is an HIV protease inhibitor and cobicistat is an inhibitor of cytochrome P450 (CYP) enzymes of the CYP3A family.

Darunavir/cobicistat, sold under the brand names Prezcobix (US) and Rezolsta (EU), is a fixed-dose combination antiretroviral medication used to treat and prevent HIV/AIDS. It contains darunavir and cobicistat. Darunavir is an HIV protease inhibitor and cobicistat increases the effectiveness of darunavir by blocking its metabolism by the enzyme CYP3A.

References

  1. ↑ Mathias AA, German P, Murray BP, Wei L, Jain A, West S, et al. (March 2010). "Pharmacokinetics and pharmacodynamics of GS-9350: a novel pharmacokinetic enhancer without anti-HIV activity". Clinical Pharmacology and Therapeutics. 87 (3): 322–9. doi:10.1038/clpt.2009.228. PMID   20043009. S2CID   29197109.
  2. 1 2 Highleyman, L. Elvitegravir "Quad" Single-tablet Regimen Shows Continued HIV Suppression at 48 Weeks Archived 3 March 2016 at the Wayback Machine . HIV and Hepatitis.com
  3. ↑ R Elion, J Gathe, B Rashbaum, and others. The Single-Tablet Regimen of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate (EVG/COBI/FTC/TDF; Quad) Maintains a High Rate of Virologic Suppression, and Cobicistat (COBI) is an Effective Pharmacoenhancer Through 48 Weeks. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2010). Boston, September 12–15, 2010.
  4. ↑ "Symtuza (cobicistat, darunavir, emtricitabine and tenofovir alafenamide) FDA Approval History". Drugs.com. Retrieved 30 October 2019.
  5. ↑ Lepist EI, Phan TK, Roy A, Tong L, Maclennan K, Murray B, Ray AS (October 2012). "Cobicistat boosts the intestinal absorption of transport substrates, including HIV protease inhibitors and GS-7340, in vitro". Antimicrobial Agents and Chemotherapy. 56 (10): 5409–13. doi:10.1128/AAC.01089-12. PMC   3457391 . PMID   22850510.
  6. ↑ Xu L, Liu H, Murray BP, Callebaut C, Lee MS, Hong A, et al. (August 2010). "Cobicistat (GS-9350): A Potent and Selective Inhibitor of Human CYP3A as a Novel Pharmacoenhancer". ACS Medicinal Chemistry Letters. 1 (5): 209–13. doi:10.1021/ml1000257. PMC   4007915 . PMID   24900196.
  7. ↑ "WO 2016128885" (PDF). Archived from the original (PDF) on 14 August 2019. Retrieved 31 August 2017.
  8. ↑ Xu L, Liu H, Hong A, Vivian R, Murray BP, Callebaut C, et al. (February 2014). "Structure-activity relationships of diamine inhibitors of cytochrome P450 (CYP) 3A as novel pharmacoenhancers. Part II: P2/P3 region and discovery of cobicistat (GS-9350)". Bioorganic & Medicinal Chemistry Letters. 24 (3): 995–9. doi:10.1016/j.bmcl.2013.12.057. PMID   24412072.
  9. ↑ Sevrioukova IF, Poulos TL (July 2013). "Dissecting cytochrome P450 3A4-ligand interactions using ritonavir analogues". Biochemistry. 52 (26): 4474–81. doi:10.1021/bi4005396. PMID   23746300.
  10. ↑ Sevrioukova IF, Poulos TL (October 2010). "Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir". Proceedings of the National Academy of Sciences of the United States of America. 107 (43): 18422–7. Bibcode:2010PNAS..10718422S. doi: 10.1073/pnas.1010693107 . PMC   2973003 . PMID   20937904.
  11. ↑ PDB 3NXU
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.