SAQUINAVIR

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C38H50N6O5
Molecular Weight	670.8408
Optical Activity	UNSPECIFIED
Defined Stereocenters	6 / 6
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[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=QWAXKHKRTORLEM-UGJKXSETSA-N

InChI=1S/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

HIDE SMILES / InChI

Molecular Formula	C38H50N6O5
Molecular Weight	670.8408
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	6 / 6
E/Z Centers	0
Optical Activity	UNSPECIFIED

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 8228	0.5 nM [IC50]
Protease 7 Target ID: CHEMBL2366517 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20108932	Inhibitor 8228	0.4 nM [IC50]
Human immunodeficiency virus type 1 protease 35 Target ID: CHEMBL243 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17964171	Inhibitor 8228	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 8360	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 8.7886083E11

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 1709 inhibitor 1579	inhibitor 1752	inhibitor 1837	inhibitor 1599

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1509 CYP2E1 876 CYP3A5 73 CYP3A7 7 CYP2C8 901 OATP1B1 781 OATP1B3 700 OATP2B1 122 BCRP 691 OCT1 506 UGT1A1 204 UGT1A3 84 UGT1A4 77 UGT1A6 108 UGT1A9 116 UGT2B7 146	CYP3A5 391 P-gp 1527 OATP1A2 61

Drug as perpetrator

Target	Modality	Activity
UGT1A6 141	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/16118329/ Page: 5.0	little [IC50 >100 uM]
UGT1A9 121	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/16118329/ Page: 5.0	little [IC50 >100 uM]
UGT2B7 157	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/16118329/ Page: 5.0	little [IC50 >100 uM]
CYP1A2 1673	inhibitor 3240 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042821/ Page: 3.0	negligible [IC50 >100 uM]
CYP2E1 964	inhibitor 3240 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042821/ Page: 3.0	negligible [IC50 >100 uM]
CYP3A7 22	inhibitor 3240 Sources: https://onlinelibrary.wiley.com/doi/full/10.1111/j.1742-7843.2006.pto_249.x	weak [Ki 1.8 uM]
CYP2C8 955	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/17361129/	yes [IC50 1.8 uM]
UGT1A1 254	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/16118329/ Page: 5.0	yes [IC50 13 uM]
OATP1B1 796	inhibitor 3240 Sources: https://www.zora.uzh.ch/id/eprint/32186/ Page: 5.0	yes [IC50 2.1 uM]
CYP3A4 1909	inhibitor 3240 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042821/ Page: 3.0	yes [IC50 2.14 uM]
BCRP 765	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/17202245/	yes [IC50 27.4 uM]
OATP1B3 709	inhibitor 3240 Sources: https://www.zora.uzh.ch/id/eprint/32186/ Page: 5.0	yes [IC50 4.1 uM]
OATP2B1 125	inhibitor 3240 Sources: https://www.zora.uzh.ch/id/eprint/32186/ Page: 12.0	yes [IC50 5.3 uM]
UGT1A3 93	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/16118329/ Page: 5.0	yes [IC50 5.5 uM]
CYP2C9 1803	inhibitor 3240 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042821/ Page: 3.0	yes [IC50 54 uM]
UGT1A4 80	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/16118329/ Page: 5.0	yes [IC50 8 uM]
OCT1 523	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/10681378/	yes [IC50 8.3 uM]
CYP3A5 130	inhibitor 3240 Sources: https://onlinelibrary.wiley.com/doi/full/10.1111/j.1742-7843.2006.pto_249.x	yes [Ki 0.6 uM]
CYP2D6 1875	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/9758674/ Page: 3.0	yes [Ki 24 uM]

Drug as victim

Target	Modality	Activity	Clinical evidence
OATP1A2 61	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/10421612/; https://transportal.compbio.ucsf.edu/compounds/saquinavir/ Page: 5.0	yes [IC50 <10 uM]
CYP3A5 391	substrate 3326 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884607/	yes
P-gp 1527	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/9732409/	yes
CYP3A4 1709	substrate 3326 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 1632	inhibitor 1613 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
Unexplained thrombosis in HIV-infected patients receiving protease inhibitors: report of seven cases.	1999 Dec	10625032
Structural and kinetic analyses of the protease from an amprenavir-resistant human immunodeficiency virus type 1 mutant rendered resistant to saquinavir and resensitized to amprenavir.	2000 Aug	10906218
BMS-232632, a highly potent human immunodeficiency virus protease inhibitor that can be used in combination with other available antiretroviral agents.	2000 Aug	10898681
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
In-vitro tipranavir susceptibility of HIV-1 isolates with reduced susceptibility to other protease inhibitors.	2000 Jan 7	10714580
Drug resistance and drug combination features of the human immunodeficiency virus inhibitor, BCH-10652 [(+/-)-2'-deoxy-3'-oxa-4'-thiocytidine, dOTC].	2000 Jul	10950391
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
Inhibition of HIV-1 protease by a boron-modified polypeptide.	2000 Oct 1	10974201
In vitro resistance profile of the human immunodeficiency virus type 1 protease inhibitor BMS-232632.	2000 Sep	10952574
Identification of MK-944a: a second clinical candidate from the hydroxylaminepentanamide isostere series of HIV protease inhibitors.	2000 Sep 7	10978186
Tipranavir inhibits broadly protease inhibitor-resistant HIV-1 clinical samples.	2000 Sep 8	10997398
Comparison of P-triglyceride levels among patients with human immunodeficiency virus on randomized treatment with ritonavir, indinavir or ritonavir/saquinavir.	2001	11345223
Analysis of HIV-1 mutation patterns in patients failing antiretroviral therapy.	2001	11170234
Generation of a flexible cell line with regulatable, high-level expression of HIV Gag/Pol particles capable of packaging HIV-derived vectors.	2001 Apr	11319923
P-glycoprotein limits oral availability, brain, and fetal penetration of saquinavir even with high doses of ritonavir.	2001 Apr	11259625
Determination of serum levels of thirteen human immunodeficiency virus-suppressing drugs by high-performance liquid chromatography.	2001 Apr 13	11355843
[Improving the pharmacokinetics of protease inhibitors in a more innovative manner. HIV drugs administered in a more clever way].	2001 Apr 2	11373769
Antiviral drugs: current state of the art.	2001 Aug	11418355
Pharmacology and clinical experience with saquinavir.	2001 Feb	11336588
Pharmacokinetics of ritonavir and saquinavir in a haemodialysis patient.	2001 Feb	11244316
Ritonavir, efavirenz, and nelfinavir inhibit CYP2B6 activity in vitro: potential drug interactions with bupropion.	2001 Feb	11159797
Progressive human immunodeficiency virus-specific immune recovery with prolonged viral suppression.	2001 Feb 15	11170979
Large hepatic mitochondrial DNA deletions associated with L-lactic acidosis and highly active antiretroviral therapy.	2001 Feb 16	11273225
Ritonavir-induced carbamazepine toxicity.	2001 Jan	11197575
Effect of alpha1-acid glycoprotein on the intracellular accumulation of the HIV protease inhibitors saquinavir, ritonavir and indinavir in vitro.	2001 Jan	11167671
Pilot study of a combination of highly active antiretroviral therapy and cytokines to induce HIV-1 remission.	2001 Jan 1	11176268
Patterns of resistance mutations to antiretroviral drugs in extensively treated HIV-1-infected patients with failure of highly active antiretroviral therapy.	2001 Jan 1	11176267
Efficacy, tolerance, and pharmacokinetics of the combination of stavudine, nevirapine, nelfinavir, and saquinavir as salvage regimen after ritonavir or indinavir failure.	2001 Jan 20	11177388
The use of and response to second-line protease inhibitor regimens: results from the EuroSIDA study.	2001 Jan 26	11216928
Predictors of protease inhibitor-associated adverse events.	2001 Jul	11478584
Combination therapy with saquinavir soft gelatin capsules in children with human immunodeficiency virus infection.	2001 Jul	11465838
CMVR diagnoses and progression of CD4 cell counts and HIV viral load measurements in HIV patients on HAART.	2001 Jul	11423459
Synthesis of a chiral aziridine derivative as a versatile intermediate for HIV protease inhibitors.	2001 Jul 26	11463313
The effect of fluconazole on ritonavir and saquinavir pharmacokinetics in HIV-1-infected individuals.	2001 Jun	11422025
Prognostic factors of combined viral load and CD4+ cell count responses under triple antiretroviral therapy, Aquitaine cohort, 1996-1998.	2001 Jun 1	11404538
Effect of ritonavir/saquinavir on stereoselective pharmacokinetics of methadone: results of AIDS Clinical Trials Group (ACTG) 401.	2001 Jun 1	11404537
The effect of nevirapine in combination with nelfinavir in heavily pretreated HIV-1-infected patients: a prospective, open-label, controlled, randomized study.	2001 Jun 1	11404533
A comprehensive account on the role of efflux transporters in the gastrointestinal absorption of 13 commonly used substrate drugs in humans.	2001 Mar	11396754
The safety and antiviral effect of protease inhibitors in children.	2001 Mar	11253853
Elevated alpha-1-acid glycoprotein reduces the volume of distribution and systemic clearance of saquinavir.	2001 Mar	11181499
Sequencing of protease inhibitor therapy: insights from an analysis of HIV phenotypic resistance in patients failing protease inhibitors.	2001 Mar 30	11316998
Structure-activity studies of FIV and HIV protease inhibitors containing allophenylnorstatine.	2001 May	11377177
Secreted aspartic proteases of Candida albicans, Candida tropicalis, Candida parapsilosis and Candida lusitaniae. Inhibition with peptidomimetic inhibitors.	2001 May	11322888
Regulation of expression of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue: tissue-specific induction by cytokines.	2001 May	11316764
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
[Drug interactions with antiretroviral agents].	2001 May-Jun	11475806
Mismatched double-stranded RNA (polyI-polyC(12)U) is synergistic with multiple anti-HIV drugs and is active against drug-sensitive and drug-resistant HIV-1 in vitro.	2001 Sep	11448730

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.

Substance Class	Chemical Created by `admin` on `Wed Jul 05 23:07:37 UTC 2023` Edited by `admin` on `Wed Jul 05 23:07:37 UTC 2023`
Record UNII	L3JE09KZ2F
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

SAQUINAVIR

Official Name

English

RO 31-8959/000

Code

English

SAQUINAVIR [JAN]

Common Name

English

SAQUINAVIRUM [WHO-IP LATIN]

Common Name

English

SAQUINAVIR [ORANGE BOOK]

Common Name

English

SAQUINAVIR [VANDF]

Common Name

English

SAQUINAVIR [USAN]

Common Name

English

SAQUINAVIR [HSDB]

Common Name

English

RO-31-8959/000

Code

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.))-

Common Name

English

Saquinavir [WHO-DD]

Common Name

English

(S)-N-[(IS)-I-[(1R)-2-[(3S,4aS,8aS)-3-(tert-Butylcarbamoyl)octahydro-2(1H)-isoquinolyl]-1-hydroxyethyl]phenethyl]-2-quinaldamidosuccinamide

Common Name

English

SAQUINAVIR [USP IMPURITY]

Common Name

English

SAQUINAVIR [WHO-IP]

Common Name

English

SAQUINAVIR [EMA EPAR]

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

Common Name

English

saquinavir [INN]

Common Name

English

SAQUINAVIR [MART.]

Common Name

English

SCH-52852

Code

English

SAQUINAVIR [MI]

Common Name

English

Classification Tree Code System Code

NDF-RT

N0000175889