127779-20-8 Usage
Description
Saquinavir, also known as Saquinavir mesylate, is an aspartic acid derivative and the first HIV protease inhibitor to reach the market. It is a potent and competitive inhibitor of HIV-1 and HIV-2 proteases, with high specificity. Saquinavir inhibits the last stage in the replication process of HIV, preventing virion maturation in both acute and chronically infected cells. It is well tolerated and can be used in combination with other antiretroviral drugs to minimize resistance.
Uses
Used in Antiviral Applications:
Saquinavir is used as an antiviral agent for the treatment of advanced HIV infection. It acts as an HIV protease inhibitor, lowering p24 antigen levels in HIV-infected patients, elevating CD4+ counts, and exerting a synergistic antiviral effect when combined with reverse transcriptase inhibitors such as AZT and ddC.
Used in Combination Therapy:
Saquinavir is used in combination with approved nucleoside analogs, such as zidovudine (AZT) or/and zalcitabine, to target different stages of the HIV replication process. This combination therapy shows a greater than additive effect in increasing CD4 cell counts and reducing viral load, with the combination delaying the onset of resistance to either drug alone.
Used in Pharmaceutical Industry:
Saquinavir is used as an active pharmaceutical ingredient in the development of antiretroviral drugs. It is available in the form of Invirase (hard capsule) and Fortovase (soft capsule), both manufactured by Roche. The drug is extensively metabolized by the first-pass effect, with bioavailability ranging from 4% for the hard capsule to 12% to 15% for the soft capsule.
Originator
Roche (Switzerland)
Indications
Saquinavir is a potent inhibitor of HIV-1 and HIV-2
protease. Fortovase, a soft gel preparation of saquinavir,
has largely replaced saquinavir mesylate capsules
(Invirase) because it has improved bioavailability.
Saquinavir is usually well tolerated and most frequently
produces mild gastrointestinal side effects.
Acquired resistance
Resistance is associated with an amino acid substitution at
position 48 in the HIV protease (G48V). An L90M mutation
also confers resistance, as it does for most protease inhibitors.
Saquinavir-resistant isolates from patients on long-term therapy
often show cross-resistance to other protease inhibitors.
Pharmaceutical Applications
A peptidomimetic protease inhibitor formulated as the mesylate
for oral use.
Pharmacokinetics
Oral absorption: c. 4%
Cmax 1200 mg thrice daily: c. 1–2.2 mg/L
Cmin 1200 mg thrice daily: c. 0.1–0.22 mg/L
Plasma half-life: c. 7–12 h
Volume of distribution: c. 700 L
Plasma protein binding: c. 98%
Absorption and distribution
It is poorly absorbed and penetrates poorly into the CNS. The semen:plasma ratio is 0.04. It is not known if it is distributed into human breast milk.
Metabolism and excretion
It is metabolized via CYP3A4, principally to mono- and dihydroxylated derivatives. Around 88% of the dose is excreted in feces and 1% in urine. Caution should be exercised in severe renal impairment and moderate hepatic impairment; use in decompensated hepatic impairment is contraindicated.
Clinical Use
Treatment of HIV infection (in combination with other antiretroviral drugs)
Side effects
The most frequently reported adverse effects include abdominal
discomfort, diarrhea and nausea. Ritonavir-boosted saquinavir
is associated with a dyslipidemic profile characteristic of those
treated with a boosted protease inhibitor requiring 200 mg of
the ritonavir ‘booster’.
Drug interactions
Potentially hazardous interactions with other drugs
Analgesics: increased risk of ventricular arrhythmias
with alfentanil, fentanyl and methadone - avoid.
Anti-arrhythmics: increased risk of ventricular
arrhythmias with amiodarone, disopyramide,
dronedarone, flecainide, lidocaine or propafenone -
avoid.
Antibacterials: increased risk of ventricular
arrhythmias with clarithromycin, dapsone,
erythromycin or moxifloxacin - avoid; increased
risk of ventricular arrhythmias with delamanid;
concentration of rifabutin increased; rifampicin and
rifabutin can reduce saquinavir levels by 80% and
40% respectively (metabolism accelerated); increased
hepatoxicity with rifampicin - avoid; concentration
of both drugs increased with fusidic acid.
Anticoagulants: avoid with apixaban and
rivaroxaban.
Antidepressants: increased risk of ventricular
arrhythmias with trazodone or tricyclics - avoid;
concentration reduced by St John’s wort - avoid.
Antiepileptics: carbamazepine, phenobarbital,
and phenytoin and possibly primidone can reduce
saquinavir levels.
Antifungals: concentration increased by ketoconazole
- avoid.
Antihistamines: increased risk of ventricular
arrhythmias with mizolastine - avoid.
Antimalarials: avoid with piperaquine with
artenimol; use artemether/lumefantrine with
caution; increased risk of ventricular arrhythmias
with quinine - avoid.
Antipsychotics: increased risk of ventricular
arrhythmias with clozapine, haloperidol or
phenothiazines - avoid; possibly increased risk
of ventricular arrhythmias with pimozide and
quetiapine - avoid; possibly inhibits aripiprazole
metabolism - reduce aripiprazole dose; possibly
increases lurasidone concentration - avoid.
Antivirals: tipranavir and efavirenz can reduce
saquinavir levels; increased risk of ventricular
arrhythmias with atazanavir or lopinavir - avoid;
concentration increased by indinavir and ritonavir;
reduced darunavir concentration; concentration
of maraviroc increased, consider reducing dose of
maraviroc.
Anxiolytics and hypnotics: midazolam concentration
possibly increased (prolonged sedation) - avoid with
oral midazolam. Beta-blockers: increased risk of ventricular
arrhythmias with sotalol - avoid.
Ciclosporin: concentration of both drugs increased.
Cytotoxics: possibly increases concentration of
axitinib, ibrutinib and panobinostat, reduce dose
of axitinib, ibrutinib and panobinostat; possibly
increases bosutinib, cabazitaxel, ceritinib and
docetaxel concentration - avoid or consider reducing
dose; possibly increases concentration of crizotinib
and everolimus - avoid; avoid with lapatinib,
olaparib and pazopanib; reduce dose of ruxolitinib.
Dapoxetine: increased risk of toxicity - avoid.
Domperidone: possibly increases risk of ventricular
arrhythmias - avoid.
Ergot alkaloids: risk of ergotism - avoid.
Guanfacine: concentration possibly increased - halve
guanfacine dose.
Lipid-lowering drugs: increased risk of myopathy
with rosuvastatin and simvastatin - avoid; possibly
increased myopathy with atorvastatin; avoid with
lomitapide.
Naloxegol: possibly increases naloxegol concentration
- avoid.
Orlistat: absorption possibly reduced by orlistat.
Pentamidine: increased risk of ventricular
arrhythmias - avoid.
Ranolazine: possibly increases ranolazine
concentration - avoid.
Metabolism
Saquinavir is absorbed to a limited extent (about 30%)
after oral doses of the mesilate and undergoes extensive
first-pass hepatic metabolism via cytochrome P450
isoenzyme, CYP3A4 to form a range of mono- and
di-hydroxylated inactive compounds.
It is excreted mainly in the faeces.
Check Digit Verification of cas no
The CAS Registry Mumber 127779-20-8 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,2,7,7,7 and 9 respectively; the second part has 2 digits, 2 and 0 respectively.
Calculate Digit Verification of CAS Registry Number 127779-20:
(8*1)+(7*2)+(6*7)+(5*7)+(4*7)+(3*9)+(2*2)+(1*0)=158
158 % 10 = 8
So 127779-20-8 is a valid CAS Registry Number.
InChI:InChI=1/C38H50N6O5/c1-38(2,3)43-37(49)32-20-26-14-7-8-15-27(26)22-44(32)23-33(45)30(19-24-11-5-4-6-12-24)41-36(48)31(21-34(39)46)42-35(47)29-18-17-25-13-9-10-16-28(25)40-29/h4-6,9-13,16-18,26-27,30-33,45H,7-8,14-15,19-23H2,1-3H3,(H2,39,46)(H,41,48)(H,42,47)(H,43,49)/t26-,27+,30-,31-,32-,33+/m0/s1
127779-20-8Relevant articles and documents
NOVEL POLYMORPHS OF SAQUINAVIR
-
Page/Page column 3, (2012/02/15)
The present invention provides novel polymorphs of saquinavir, processes for their preparation and pharmaceutical compositions comprising them. The present invention also provides a process for purification of saquinavir. The present invention further provides a novel process for preparation of known saquinavir crystalline form I.
A PROCESS FOR THE PREPARATION OF SAQUINAVIR USING NOVEL INTERMEDIATE
-
Page/Page column 4-5, (2008/06/13)
The present invention provides a commercially viable process for preparing saquinavir and pharmaceutically acceptable acid addition salts thereof using novel intermediate. Thus, for example, N?2?-(2-quinolinylcarbonyl)-L-asparagine is reacted with pivaloyl chloride in methylene chloride in presence of triethyl amine to give pivaloyl N?2?-(2-quinolinylcarbonyl)-L-asparaginate, which is then condensed with [3S,4aS,8aS]-2-(3S-amino-2R-hydroxy-4-phenylbutyl)-N-(1,1-dimethylethyl)decahydro-3-isoquinoline carboxamide to give saquinavir, followed by treatment with methanesulfonic acid to give saquinavir mesylate.
Synthesis of the HIV-proteinase inhibitor Saquinavir: A challenge for process research
Goehring, Wolfgang,Gokhale, Surendra,Hilpert, Hans,Roessler, Felix,Schlageter, Markus,Vogt, Peter
, p. 532 - 537 (2007/10/03)
The task of process research, namely developing efficient, economically and technically as well as ecologically feasible syntheses in time, is demonstrated on the HIV-proteinase inhibitor Saquinavir (1), a complex molecule comprising six stereo-centres. Based on the first 26-step research synthesis furnishing a 10% overall yield, process research established a new, short 11-step synthesis affording a 50% overall yield.
