SAQUINAVIR MESYLATE

US Previously Marketed

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C38H50N6O5.CH4O3S
Molecular Weight	766.946
Optical Activity	UNSPECIFIED
Defined Stereocenters	6 / 6
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CS(O)(=O)=O.[H][C@@]12CCCC[C@]1([H])CN(C[C@@H](O)[C@H](CC3=CC=CC=C3)NC(=O)[C@H](CC(N)=O)NC(=O)C4=CC=C5C=CC=CC5=N4)[C@@H](C2)C(=O)NC(C)(C)C

InChI

InChIKey=IRHXGOXEBNJUSN-YOXDLBRISA-N

InChI=1S/C38H50N6O5.CH4O3S/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;1-5(2,3)4/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);1H3,(H,2,3,4)/t26-,27+,30-,31-,32-,33+;/m0./s1

HIDE SMILES / InChI

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021785s001,002,020828s019,020,020628s022,023lbl.pdf
Curator's Comment: description was created based on several sources, including https://www.drugbank.ca/drugs/DB01232 | http://reference.medscape.com/drug/invirase-saquinavir-342628 | https://www.drugs.com/cdi/saquinavir.html | https://www.ncbi.nlm.nih.gov/pubmed/20950334

Saquinavir (brand names Invirase and Fortovase) is an antiretroviral drug used together with other medications to treat or prevent HIV/AIDS. Saquinavir is an inhibitor of HIV protease. HIV protease is an enzyme required for the proteolytic cleavage of viral polyprotein precursors into individual functional proteins found in infectious HIV. Saquinavir is a peptide-like substrate analog that binds to the protease active site and inhibits the activity of the enzyme. Saquinavir inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature noninfectious virus particles. 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.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Human immunodeficiency virus type 2 pol protein 2 Target ID: CHEMBL5074 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8360874	Inhibitor 8297	0.5 nM [IC50]
Protease 7 Target ID: CHEMBL2366517 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20108932	Inhibitor 8297	0.4 nM [IC50]
Human immunodeficiency virus type 1 protease 35 Target ID: CHEMBL243 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17964171	Inhibitor 8297	0.4 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
HIV infection 21 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021785s001,002,020828s019,020,020628s022,023lbl.pdf	Primary		Approved 8429	FORTOVASE Approved Use INDICATIONS & USAGE INVIRASE in combination with ritonavir and other antiretroviral agents is indicated for the treatment of HIV-1 infection in adults (over the age of 16 years). The following points should be considered when initiating therapy with INVIRASE: – The twice daily administration of INVIRASE in combination with ritonavir is supported by safety data from the MaxCmin 1 trial [see Adverse Reactions (6.1) Launch Date 1997

AUC

Value	Dose	Co-administered	Analyte	Population
21747 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021785s001,002,020828s019,020,020628s022,023lbl.pdf	1200 mg 3 times / day steady-state, oral dose: 1200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		SAQUINAVIR unknown	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
1000 mg 2 times / day multiple, oral Recommended Dose: 1000 mg, 2 times / day Route: oral Route: multiple Dose: 1000 mg, 2 times / day Co-administed with:: ritonavir(100 mg; 2/day) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020628s034-021785s011lbl.pdf	unhealthy, adult n = 148 Health Status: unhealthy Condition: HIV-1 infection Age Group: adult Population Size: 148 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020628s034-021785s011lbl.pdf	Other AEs: Diabetes mellitus, Lipodystrophy... Other AEs: Diabetes mellitus (3%) Lipodystrophy (5%) Nausea (11%) Vomiting (7%) Diarrhea (8%) Abdominal pain (6%) Constipation (2%) Fatigue (6%) Fever (3%) Back pain (2%) Pneumonia (5%) Bronchitis (3%) Influenza (3%) Sinusitis (3%) Rash (3%) Pruritus (3%) Dry lips (2%) Eczema (2%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020628s034-021785s011lbl.pdf
1600 mg 1 times / day multiple, oral Dose: 1600 mg, 1 times / day Route: oral Route: multiple Dose: 1600 mg, 1 times / day Co-administed with:: ritonavir(100 mg; 1/day) Sources: https://pubmed.ncbi.nlm.nih.gov/16926775/	unhealthy, adult n = 81 Health Status: unhealthy Condition: HIV-1 infection Age Group: adult Sex: M+F Population Size: 81 Sources: https://pubmed.ncbi.nlm.nih.gov/16926775/	Other AEs: Nausea, Vomiting... Other AEs: Nausea (22.2%) Vomiting (6.2%) Diarrhea (4.9%) Abdominal pain (2.5%) Diarrhea aggravated (2.5%) Esophageal reflux (2.5%) Fatigue (2.5%) Dizziness (excl vertigo) (1.2%) Dermatitis (1.2%) Decreased appetite (3.7%) Headache (2.5%) Insomnia (1.2%) Weakness (2.5%) Depression (2.5%) Anxiety (1.2%) Sources: https://pubmed.ncbi.nlm.nih.gov/16926775/

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587	inhibitor 1767	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2E1 882 CYP3A5 73 CYP3A7 7 CYP2C8 911 OATP1B1 788 OATP1B3 706 OATP2B1 123 BCRP 699 OCT1 512 UGT1A1 204 UGT1A3 84 UGT1A4 77 UGT1A6 108 UGT1A9 116 UGT2B7 146	CYP3A5 395 P-gp 1537 OATP1A2 62

Drug as perpetrator

Target	Modality	Activity
UGT1A6 141	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/16118329/ Page: 5.0	little [IC50 >100 uM]
UGT1A9 121	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/16118329/ Page: 5.0	little [IC50 >100 uM]
UGT2B7 157	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/16118329/ Page: 5.0	little [IC50 >100 uM]
CYP1A2 1692	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042821/ Page: 3.0	negligible [IC50 >100 uM]
CYP2E1 970	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042821/ Page: 3.0	negligible [IC50 >100 uM]
CYP3A7 22	inhibitor 3277 Sources: https://onlinelibrary.wiley.com/doi/full/10.1111/j.1742-7843.2006.pto_249.x	weak [Ki 1.8 uM]
CYP2C8 965	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/17361129/	yes [IC50 1.8 uM]
UGT1A1 254	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/16118329/ Page: 5.0	yes [IC50 13 uM]
OATP1B1 803	inhibitor 3277 Sources: https://www.zora.uzh.ch/id/eprint/32186/ Page: 5.0	yes [IC50 2.1 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042821/ Page: 3.0	yes [IC50 2.14 uM]
BCRP 773	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/17202245/	yes [IC50 27.4 uM]
OATP1B3 715	inhibitor 3277 Sources: https://www.zora.uzh.ch/id/eprint/32186/ Page: 5.0	yes [IC50 4.1 uM]
OATP2B1 126	inhibitor 3277 Sources: https://www.zora.uzh.ch/id/eprint/32186/ Page: 12.0	yes [IC50 5.3 uM]
UGT1A3 93	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/16118329/ Page: 5.0	yes [IC50 5.5 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042821/ Page: 3.0	yes [IC50 54 uM]
UGT1A4 80	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/16118329/ Page: 5.0	yes [IC50 8 uM]
OCT1 543	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/10681378/	yes [IC50 8.3 uM]
CYP3A5 130	inhibitor 3277 Sources: https://onlinelibrary.wiley.com/doi/full/10.1111/j.1742-7843.2006.pto_249.x	yes [Ki 0.6 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/9758674/ Page: 3.0	yes [Ki 24 uM]

Drug as victim

Target	Modality	Activity	Clinical evidence
OATP1A2 62	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10421612/; https://transportal.compbio.ucsf.edu/compounds/saquinavir/ Page: 5.0	yes [IC50 <10 uM]
CYP3A5 395	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884607/	yes
P-gp 1537	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/9732409/	yes
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021785s001,002,020828s019,020,020628s022,023lbl.pdf#page=13 Page: 13,19	yes	yes (co-administration study) Comment: Coadministration with ritonavir (CYP3A4 inhibitor): mean saquinavir AUC value was seven fold greater than mean value observed after administration of saquinavir alone. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021785s001,002,020828s019,020,020628s022,023lbl.pdf#page=13 Page: 13,19

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://pubmed.ncbi.nlm.nih.gov/15721475/ Page: 3.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:63621	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:63621
ChemicalBook	CB2161048	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB2161048
MolPort	MolPort-000-883-824	https://www.molport.com/shop/molecule-link/MolPort-000-883-824
ZINC	ZINC000003914596	http://zinc15.docking.org/substances/ZINC000003914596
eMolecules	27523858	https://www.emolecules.com/cgi-bin/more?vid=27523858
eMolecules	30512889	https://www.emolecules.com/cgi-bin/more?vid=30512889

PubMed

Title	Date	PubMed
Anti-HIV activity and mechanism of action of macrocyclic diamide SRR-SB3.	1998 Dec	10052846
Non-active site changes elicit broad-based cross-resistance of the HIV-1 protease to inhibitors.	1999 Aug 20	10446127
Cage dimeric 4-aryl-1,4-dihydropyridines as promising lead structures for the development of a novel class of HIV-1 protease inhibitors.	1999 Jan	10073137
Pyrido [1,2a] indole derivatives identified as novel non-nucleoside reverse transcriptase inhibitors of human immunodeficiency virus type 1.	1999 Mar	10335402
The HIV type 1 protease inhibitor saquinavir can select for multiple mutations that confer increasing resistance.	1999 Mar 1	10082119
A new class of anti-HIV agents: synthesis and activity of conjugates of HIV protease inhibitors with a reverse transcriptase inhibitor.	1999 Mar 22	10206539
Inhibitory effect of human immunodeficiency virus protease inhibitors on multidrug resistance transporter P-glycoproteins.	2000 Dec	11145192
Increasing cerebrospinal fluid chemokine concentrations despite undetectable cerebrospinal fluid HIV RNA in HIV-1-infected patients receiving antiretroviral therapy.	2000 Dec 15	11141242
Drug resistance and drug combination features of the human immunodeficiency virus inhibitor, BCH-10652 [(+/-)-2'-deoxy-3'-oxa-4'-thiocytidine, dOTC].	2000 Jul	10950391
Novel inhibitors of HIV protease: design, synthesis and biological evaluation of picomolar inhibitors containing cyclic P1/P2 scaffolds.	2000 Jun 5	10866371
In vitro activity of human immunodeficiency virus protease inhibitors against Pneumocystis carinii.	2000 May	10823762
A mutation in human immunodeficiency virus type 1 protease, N88S, that causes in vitro hypersensitivity to amprenavir.	2000 May	10756056
Tipranavir inhibits broadly protease inhibitor-resistant HIV-1 clinical samples.	2000 Sep 8	10997398
Analysis of HIV-1 mutation patterns in patients failing antiretroviral therapy.	2001	11170234
High prevalence of genotypic and phenotypic HIV-1 drug-resistant strains among patients receiving antiretroviral therapy in Abidjan, Côte d'Ivoire.	2001 Apr 15	11391173
Pharmacokinetics and resistance mutations affect virologic response to ritonavir/saquinavir-containing regimens.	2001 Aug	11477313
HIV-protease inhibitors contribute to P-glycoprotein efflux function defect in peripheral blood lymphocytes from HIV-positive patients receiving HAART.	2001 Aug 1	11468419
[Resistance to protease inhibitors].	2001 Feb	11428058
Ritonavir, efavirenz, and nelfinavir inhibit CYP2B6 activity in vitro: potential drug interactions with bupropion.	2001 Feb	11159797
Large hepatic mitochondrial DNA deletions associated with L-lactic acidosis and highly active antiretroviral therapy.	2001 Feb 16	11273225
Effect of alpha1-acid glycoprotein on the intracellular accumulation of the HIV protease inhibitors saquinavir, ritonavir and indinavir in vitro.	2001 Jan	11167671
The use of and response to second-line protease inhibitor regimens: results from the EuroSIDA study.	2001 Jan 26	11216928
Maternal-fetal transfer of saquinavir studied in the ex vivo placental perfusion model.	2001 Jul	11483925
Capillary electrophoretic separation of protease inhibitors used in human immunodeficiency virus therapy.	2001 Jul 13	11486877
High-performance liquid chromatographic assay to determine the plasma levels of HIV-protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir and saquinavir) and the non-nucleoside reverse transcriptase inhibitor (nevirapine) after liquid-liquid extraction.	2001 Jul 15	11486821
Synthesis of a chiral aziridine derivative as a versatile intermediate for HIV protease inhibitors.	2001 Jul 26	11463313
Simultaneous determination of the HIV-protease inhibitors indinavir, amprenavir, ritonavir, saquinavir and nelfinavir in human plasma by reversed-phase high-performance liquid chromatography.	2001 Jun 15	11417878
A distinct binding mode of a hydroxyethylamine isostere inhibitor of HIV-1 protease.	2001 Mar	11223536
Elevated alpha-1-acid glycoprotein reduces the volume of distribution and systemic clearance of saquinavir.	2001 Mar	11181499
Increased risk of lipodystrophy when nucleoside analogue reverse transcriptase inhibitors are included with protease inhibitors in the treatment of HIV-1 infection.	2001 May 4	11399957
Simultaneous determination of the HIV protease inhibitors indinavir, amprenavir, saquinavir, ritonavir and nelfinavir in human plasma by high-performance liquid chromatography.	2001 May 5	11393736
Combined hydroxypropyl-beta-cyclodextrin and poly(alkylcyanoacrylate) nanoparticles intended for oral administration of saquinavir.	2001 May 7	11337155

Patents

Sample Use Guides

In Vivo Use Guide

1000 mg (with ritonavir 100 mg) PO q12hr, or in combination with ritonavir-enhanced lopinavir Treatment-naïve patients: Initial dose: 500 mg PO BID plus ritonavir 100 mg BID x 7 days, THEN increase to 1000mg/100mg PO BID

Route of Administration: Oral

In Vitro Use Guide

In vitro antiviral activity of saquinavir was assessed in lymphoblastoid and monocytic cell lines and in peripheral blood lymphocytes. Saquinavir inhibited HIV activity in both acutely and chronically infected cells. IC50 and IC90 values (50% and 90% inhibitory concentrations) were in the range of 1 to 30 nM and 5 to 80 nM, respectively. In the presence of 40% human serum, the mean IC50 of saquinavir against laboratory strain HIV-1 RF in MT4 cells was 37.7± 5nM representing a 4-fold increase in the IC50 value. In cell culture, saquinavir demonstrated additive to synergistic effects against HIV-1 in combination with reverse transcriptase inhibitors (didanosine, lamivudine, nevirapine, stavudine, zalcitabine and zidovudine) without enhanced cytotoxicity. Saquinavir in combination with the protease inhibitors amprenavir, atazanavir, or lopinavir resulted in synergistic antiviral activity. Saquinavir displayed antiviral activity in vitro against HIV-1 clades A-H (IC50 ranged from 0.9 to 2.5 nM). The IC50 and IC90 values of saquinavir against HIV-2 isolates in vitro ranged from 0.25 nM to 14.6 nM and 4.65 nM to 28.6 nM respectively.

Name

Type

Language

SAQUINAVIR MESYLATE

Official Name

English

SAQUINAVIR MESILATE [EP MONOGRAPH]

Common Name

English

SAQUINAVIR MESYLATE [USP MONOGRAPH]

Common Name

English

(S)-N-((.ALPHA.S)-.ALPHA.-((1R)-2-((3S,4AS,8AS)-3-(TERT-BUTYLCARBAMOYL)OCTAHYDRO-2(1H)-ISOQUINOLYL)-1-HYDROXYETHYL)PHENETHYL)-2-QUINALDAMIDOSUCCINAMIDE MONOMETHANESULFONATE

Common Name

English

RO 31-8959/003

Code

English

SAQUINAVIR METHANESULFONATE SALT [MI]

Common Name

English

SAQUINAVIR MESYLATE [USP-RS]

Common Name

English

SAQUINAVIR MESILATE [JAN]

Common Name

English

Saquinavir mesilate [WHO-DD]

Common Name

English

SAQUINAVIR MESYLATE [USP IMPURITY]

Common Name

English

SAQUINAVIR MESILATE [MART.]

Common Name

English

SAQUINAVIR MESYLATE [VANDF]

Common Name

English

SAQUINAVIR MESILATE

Common Name

English

RO-318959003

Code

English

RO-31-8959/003

Code

English

SAQUINAVIR MESYLATE [USAN]

Common Name

English

BUTANEDIAMIDE, N(SUP 1)-(3-(3-(((1,1-DIMETHYLETHYL)AMINO)CARBONYL)OCTAHYDRO-2(1H)-ISOQUINOLINYL)-2-HYDROXY-1-(PHENYLMETHYL)PROPYL)-2-((2-QUINOLINYLCARBONYL)AMINO)-, (3S-(2(1R*(R*),2S*),3.ALPHA.,4A.BETA.,8A.BETA.))-, MONOMETHANESULPHONATE

Common Name

English

BUTANEDIAMIDE, N(SUP 1)-(3-(3-(((1,1-DIMETHYLETHYL)AMINO)CARBONYL)OCTAHYDRO-2(1H)-ISOQUINOLINYL)-2-HYDROXY-1-(PHENYLMETHYL)PROPYL)-2-((2-QUINOLINYLCARBONYL)AMINO)-, (3S-(2(1R*(R*),2S*),3.ALPHA.,4A.BETA.,8A.BETA.))-, MONOMETHANESULFONATE

Common Name

English

(S)-N-((.ALPHA.S)-.ALPHA.-((1R)-2-((3S,4AS,8AS)-3-(TERT-BUTYLCARBAMOYL)OCTAHYDRO-2(1H)-ISOQUINOLYL)-1-HYDROXYETHYL)PHENETHYL)-2-QUINALDAMIDOSUCCINAMIDE MONOMETHANESULPHONATE

Common Name

English

SAQUINAVIR MESILATE [WHO-IP]

Common Name

English

SAQUINAVIR MESYLATE [ORANGE BOOK]

Common Name

English

SAQUINAVIR METHANESULFONATE SALT

Common Name

English

INVIRASE

Brand Name

English

Classification Tree Code System Code

EMA ASSESSMENT REPORTS

INVIRASE (AUTHORIZED: HIV INFECTIONS)