1004316-88-4 Usage
Description
Cobicistat (GS-9350) is a potent and selective inhibitor of CYP3A with IC50 of 30-285 nM. It is a selective, mechanism-based CYP3A inhibitor, discovered and developed by Gilead Sciences, Inc. Cobicistat does not interact with HIV directly but serves as a pharmacokinetic enhancer to boost the anti-HIV effect of certain protease inhibitors through blockade of CYP3A. It is available under the brand name Tybost.
Uses
Used in HIV Treatment:
Cobicistat is used as a pharmacoenhancer for HIV protease inhibitors, such as atazanavir or darunavir, to significantly increase their plasma concentrations. It serves as a pharmacokinetic enhancer by slowing CYP-mediated metabolism of these protease inhibitors, resulting in prolonged systemic exposure of the drug(s).
Used in Isotope Labelled Applications:
Cobicistat is used as an isotope labelled analogue (C633150) for coadministration with low-dose ritonavir (R535000) as a pharmacoenhancer, significantly increasing their plasma concentrations.
Used in Mass Spectrometry:
Labeled Cobicistat is intended for use as an internal standard for the quantification of Cobicistat by GCor LC-mass spectrometry, which aids in the analysis and measurement of the compound in various samples.
Used in Fixed-Dose Combination Tablet:
Cobicistat is part of a fixed-dose combination tablet (Stribild) that includes four additional drugs with CYP3A liabilities (elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate). This combination tablet was approved in the U.S. in 2012, and subsequently in Europe and Japan in 2013, for the treatment of HIV-1 infection.
In vitro
Cobicistat (GS-9350) is a potent, and selective inhibitor of human cytochrome P450 3A (CYP3A) enzymes as a pharmacoenhancer. GS-9350 inhibits CYP3A with IC50 spectrum from 30 nM to 285 nM. In contrast to ritonavir, GS-9350 is devoid of anti-HIV activity, with IC50 of > 30μM against HIV-1 protease and EC50 of > 30μM in MT-2 HIV infection assay, and is thus more suitable for use in boosting anti-HIV drugs without risking selection of potential drug-resistant HIV variants. GS-9350 shows reduced liability for drug interactions and may have potential improvements in tolerability over ritonavir.
Originator
Gilead (United States)
Clinical Use
Pharmacokinetic enhancer used to increase the effect of
atazanavir and darunavir
Synthesis
Commercial L-methionine (24) was treated with bromoacetic
acid at elevated temperatures to afford aminolactone salt 25 in
70% yield. This material was then reacted with methyl
aminomethylthiazole (26) in the presence of CDI and diisopropylethylamine
to arrive at urea 27 in 91% yield. Next, lactone 27
underwent a ring-opening sequence upon exposure to trimethylsilyl
iodide (TMSI) giving intermediate 28. The iodide was then displaced
by morpholine, followed by treatment with oxalic acid to
deliver the L-thiazole morpholine ethyl ester as the oxalate salt 29 in 71% yield for the sequence. Base-mediated hydrolysis of ethyl
ester 29, followed by treatment of carboxylate 30 with mono-carbonate
hydrochloride 31 in the presence of EDCI and HOBT, provided
cobicistat (V) in 76% yield for two steps.
Drug interactions
Potentially hazardous interactions with other drugsAlpha-blockers: concentration of alfuzosin possibly
increased - avoid.
Anti-arrhythmics: concentration of amiodarone
possibly increased - avoid.
Antibacterials: concentration reduced by rifabutin
and rifampicin - adjust cobicistat dose, avoid with
rifampicin.
Anticoagulants: avoid with apixaban; anticoagulant
effect of rivaroxaban possibly enhanced - avoid.
Antidepressants: concentration possibly reduced by
St John’s wort - avoid.
Antiepileptics: concentration of cobicistat
possibly reduced by carbamazepine, fosphenytoin
phenobarbital, phenytoin and primidone - avoid.
Antifungals: concentration of itraconazole and
ketoconazole possibly increased - reduce antifungal
dose.
Antipsychotics: concentration of lurasidone and
pimozide possibly increased - avoid.
Antivirals: concentration of daclatasvir and
maraviroc possibly increased - reduce daclatasvir
and maraviroc dose; avoid with dasabuvir, nevirapine,
ombitasvir, paritaprevir, ritonavir and simeprevir;
concentration of elbasvir and grazoprevir increased -
avoid; concentration of olaparib possibly increased -
avoid or reduce olaparib dose; concentration of both
drugs reduced with tipranavir - avoid.
Anxiolytics: avoid with oral midazolam.
Avanafil: concentration of avanafil possibly increased
- avoid.
Bosentan: avoid concomitant use.
Cardiac glycosides: concentration of digoxin possibly
increased - reduce initial dose of digoxin.
Corticosteroids: concentration of corticosteroids
possibly increased avoid or use with caution.
Cytotoxics: concentration of ibrutinib possibly
increased - reduce ibrutinib dose; concentration of
olaparib possibly increased - avoid or reduce dose of
olaparib.
Domperidone: possible increased risk of ventricular
arrhythmias - avoid.
Ergot alkaloids: concentration of ergot alkaloids
possibly increased - avoid.
Immunosuppression: concentration of ciclosporin,
sirolimus and tacrolimus possibly increased.
Lipid-lowering drugs: concentration of atorvastatin
possibly increased - reduce atorvastatin dose; avoid
with simvastatin.
Oestrogens: metabolism of oestrogens accelerated,
reduced contraceptive effect - avoid or use with
caution. Salmeterol: avoid concomitant use.
Sildenafil: concentration of sildenafil possibly
increased - avoid sildenafil for pulmonary arterial
hypertension, reduce dose for erectile dysfunction.
Tadalafil: concentration of tadalafil possibly
increased - reduce dose of tadalafil.
Vardenafil: concentration of vardenafil possibly
increased - reduce dose of vardenafil.
Metabolism
Cobicistat is metabolised via CYP3A (major)- and
CYP2D6 (minor)-mediated oxidation. Following oral
administration of [14C]-cobicistat, 99% of circulating
radioactivity in plasma was unchanged cobicistat. Low
levels of metabolites are observed in urine and faeces and
do not contribute to the CYP3A inhibitory activity of
cobicistat.Following oral administration of [14C]-cobicistat, 86%
and 8.2% of the dose were recovered in faeces and urine,
respectively.
references
[1] deeks ed. cobicistat: a review of its use as a pharmacokinetic enhancer of atazanavir and darunavir in patients with hiv-1 infection. drugs. 2014 feb;74(2):195-206.
Check Digit Verification of cas no
The CAS Registry Mumber 1004316-88-4 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,0,0,4,3,1 and 6 respectively; the second part has 2 digits, 8 and 8 respectively.
Calculate Digit Verification of CAS Registry Number 1004316-88:
(9*1)+(8*0)+(7*0)+(6*4)+(5*3)+(4*1)+(3*6)+(2*8)+(1*8)=94
94 % 10 = 4
So 1004316-88-4 is a valid CAS Registry Number.
