Saquinavir

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Saquinavir
Saquinavir.svg
Saquinavir ball-and-stick.png
Systematic (IUPAC) name
(2S)-N-[(2S,3R)-4-[(3S)-3-(tert-butylcarbamoyl)-decahydroisoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]-2-(quinolin-2-ylformamido)butanediamide
Clinical data
Trade names Invirase
AHFS/Drugs.com monograph
MedlinePlus a696001
Pregnancy cat.
  • B1 (Australia)
Legal status
?
Pharmacokinetic data
Protein binding 98%
Half-life 9 - 15 hours
Identifiers
CAS number 127779-20-8 YesY
ATC code J05AE01
PubChem CID 441243
DrugBank DB01232
ChemSpider 390016 YesY
UNII L3JE09KZ2F YesY
KEGG D00429 YesY
ChEMBL CHEMBL114 YesY
NIAID ChemDB 000640
Chemical data
Formula C38H50N6O5 
Mol. mass 670.841 g/mol
 YesY (what is this?)  (verify)

Saquinavir is an antiretroviral drug used in HIV therapy. It falls in the protease inhibitor class. Two formulations have been marketed:

  • a hard-gel capsule formulation of the mesylate, with trade name Invirase, which requires combination with ritonavir to increase the saquinavir bioavailability;
  • a soft-gel capsule formulation of saquinavir (microemulsion,[1] orally-administered formulation), with trade name Fortovase.

Both formulations are generally used as a component of highly active antiretroviral therapy (HAART).

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[2]

Mechanism of action[edit]

Saquinavir is a protease inhibitor. Proteases are enzymes that cleave protein molecules into smaller fragments. HIV protease is vital for both viral replication within the cell and release of mature viral particles from an infected cell. Saquinavir binds to the active site of the viral protease and prevents cleavage of viral polyproteins, preventing maturation of the virus. Saquinavir inhibits both HIV-1 and HIV-2 proteases.

Adverse reactions[edit]

The most frequent adverse events with saquinavir in either formulation are mild gastrointestinal symptoms, including diarrhea, nausea, loose stools & abdominal discomfort. Invirase is better tolerated than Fortovase.

Bioavailability and drug interactions[edit]

Saquinavir, in the Invirase formulation, has a low and variable oral bioavailability, when given alone. The Fortovase formulation at the standard dosage delivers approximately eightfold more active drug than Invirase, also at the standard dosage.[3]

In the clinic, it was found that the oral bioavailability of saquinavir in both formulations significantly increases when patients also receive the PI ritonavir. For patients, this has the major benefit that they can take less saquinavir, while maintaining sufficient saquinavir blood plasma levels to efficiently suppress the replication of HIV.

The mechanism behind this welcome observation was not directly known, but later it was determined that ritonavir inhibits the cytochrome P450 3A4 isozyme. Normally, this enzyme metabolizes saquinavir to an inactive form, but with the ritonavir inhibiting this enzyme, the saquinavir blood plasma levels increased considerably. Additionally, ritonavir also inhibits multidrug transporters, although to a much lower extent.

Unlike other protease inhibitors, the absorption of saquinavir seems to be improved by omeprazole.[4]

History[edit]

Saquinavir was developed by the pharmaceutical company Roche. Saquinavir was the first protease inhibitor (and sixth antiretroviral) approved by the Food and Drug Administration (FDA). Within 2 years of its approval, and that of ritonavir 4 months later, annual deaths from AIDS in the United States fell from over 50,000 to approximately 18,000.[5] The manufacturer, Roche, requested and received approval of Invirase via the FDA's "Accelerated Approval" program, a process designed to speed drugs to market for the treatment of serious diseases. This decision was controversial, amid disagreement between AIDS activists over the benefits of thorough testing versus early access to new drugs.[6]

It was approved again on Nov 7, 1997 as Fortovase, a soft gel capsule reformulated for improved bioavailability. Roche announced in May 2005 that, owing to reduction in demand, Fortovase would cease being marketed early in 2006 in favour of Invirase boosted with ritonavir.[7]

Synthesis[edit]

The required reagent is prepared by reaction of the enolate obtained from the bis-silyl ether of glyoxylic acid and Lithium bis(trimethylsilyl)amide (LiHMDS) with trimethylsilyl chloride.

The half-acid is then resolved as its salt with l-ephedrine. The desired enantiomer is next converted to the acid chloride; hydrogenation under Rosenmund conditions, and palladium in charcoal in the presence of quinoline, lead to the aldehyde.

Saquinavir synthesis:[8][9][10] (from Lednicer Strategies book and proof-read against his sixth book.)

References[edit]

  1. ^ Gibaud, S. P.; Attivi, D. (2012). "Microemulsions for oral administration and their therapeutic applications". Expert Opinion on Drug Delivery: 1. doi:10.1517/17425247.2012.694865.  edit
  2. ^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014. 
  3. ^ FortovaseTM (saquinavir) soft gelatin capsules. Product information (November 1997)
  4. ^ Winston A, Back D, Fletcher C et al. (2006). "Effect of omeprazole on the pharmacokinetics of saquinavir-500 mg formulation with ritonavir in healthy male and female volunteers". AIDS 20 (10): 1401–6. doi:10.1097/01.aids.0000233573.41597.8a. PMID 16791014. 
  5. ^ "HIV Surveillance --- United States, 1981--2008". Retrieved 8 November 2013. 
  6. ^ "Drugs! Drugs! Drugs! An Overview of the Approved Anti-HIV Medications". The Body. Retrieved 20 February 2013. 
  7. ^ Withdrawal of Fortovase (PDF)
  8. ^ Wissner, A. (1979). "2-Heterosubstituted silylated ketone acetals: Reagents for the preparation of .alpha.-functionalized methylketones from carboxylic acid chlorides". The Journal of Organic Chemistry 44 (25): 4617. doi:10.1021/jo00393a034.  edit
  9. ^ Parkes, K. E. B.; Bushnell, D. J.; Crackett, P. H.; Dunsdon, S. J.; Freeman, A. C.; Gunn, M. P.; Hopkins, R. A.; Lambert, R. W.; Martin, J. A. (1994). "Studies toward the Large-Scale Synthesis of the HIV Proteinase Inhibitor Ro 31-8959". The Journal of Organic Chemistry 59 (13): 3656. doi:10.1021/jo00092a026.  edit
  10. ^ Houpis, I. N.; Molina, A.; Reamer, R. A.; Lynch, J. E.; Volante, R. P.; Reider, P. J. (1993). "Towards the synthesis of HIV-protease inhibitors. Synthesis optically pure 3-carboxyl-decahydroisoquinolines". Tetrahedron Letters 34 (16): 2593. doi:10.1016/S0040-4039(00)77633-7.  edit

External links[edit]

Further reading[edit]

  • Cohen Stuart JW, Schuurman R, Burger DM, et al. (1999) Randomized trial comparing saquinavir soft gelatin capsules versus indinavir as part of triple therapy (CHEESE study). AIDS 13:F53-58
  • Dragsted UB, Gerstoft J, Pedersen C, et al. (2003) Randomized trial to evaluate indinavir/ritonavir versus saquinavir/ritonavir in human immunodeficiency virus type 1-infected patients: the MaxCmin 1 Trial. J Infect Dis 188:635-642