BEVIRIMAT

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C36H56O6
Molecular Weight	584.8262
Optical Activity	UNSPECIFIED
Defined Stereocenters	10 / 10
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[H][C@]12[C@@H](CC[C@@]1(CC[C@]3(C)[C@]2([H])CC[C@]4([H])[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(O)=O)C(C)(C)[C@]5([H])CC[C@@]34C)C(O)=O)C(C)=C

InChI

InChIKey=YJEJKUQEXFSVCJ-WRFMNRASSA-N

InChI=1S/C36H56O6/c1-21(2)22-12-17-36(30(40)41)19-18-34(8)23(28(22)36)10-11-25-33(7)15-14-26(42-27(37)20-31(3,4)29(38)39)32(5,6)24(33)13-16-35(25,34)9/h22-26,28H,1,10-20H2,2-9H3,(H,38,39)(H,40,41)/t22-,23+,24-,25+,26-,28+,33-,34+,35+,36-/m0/s1

HIDE SMILES / InChI

Molecular Formula	C36H56O6
Molecular Weight	584.8262
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	9 / 10
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/14573704 | https://www.ncbi.nlm.nih.gov/pubmed/19024627 | https://www.ncbi.nlm.nih.gov/pubmed/17638699 | http://adisinsight.springer.com/drugs/800013764

Bevirimat (3-O-(3',3'-dimethylsuccinyl) betulinic acid or MPC-4326 or PA-457) potently inhibits replication of both WT and drug-resistant HIV-1 isolates and demonstrate that the compound acts by disrupting a late step in Gag processing involving conversion of the capsid precursor (p25) to mature capsid protein (p24). Bevirimat inhibits replication of both wild-type and drug-resistant HIV-1 isolates in vitro, achieving similar 50% inhibitory concentration values with both categories. Serial drug passage studies have identified six single amino acid substitutions that independently confer bevirimat resistance. These resistance mutations occur at or near the CA-SP1 cleavage site, which is not a known target for resistance to other antiretroviral drugs. Bevirimat has been in phase 2 trial for the treatment of HIV infections. Bevirimat has demonstrated a consistent pharmacokinetic profile in healthy volunteers and HIV-infected patients. The demonstration of an antiviral effect following a single oral dose of bevirimat validates maturation inhibition as a potential target for antiretroviral therapeutics in humans.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Gag-Pol polyprotein 6 Target ID: CHEMBL5823 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27893830 \| https://www.ncbi.nlm.nih.gov/pubmed/23144615 \| https://www.ncbi.nlm.nih.gov/pubmed/22151792 \| https://www.ncbi.nlm.nih.gov/pubmed/14573704	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
HIV-1 infection 151 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19024627	Primary		Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
11.9 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	BEVIRIMAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
25.1 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	BEVIRIMAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
6 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:	BEVIRIMAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
58 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104	200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BEVIRIMAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
8 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104	25 mg 1 times / day multiple, oral dose: 25 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BEVIRIMAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
31.6 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104	100 mg 1 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BEVIRIMAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
43.7 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104	150 mg 1 times / day multiple, oral dose: 150 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BEVIRIMAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Analyte	Population
180.9 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	BEVIRIMAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
382.9 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	BEVIRIMAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
88.2 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:	BEVIRIMAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
1113.7 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104	200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BEVIRIMAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
156.5 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104	25 mg 1 times / day multiple, oral dose: 25 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BEVIRIMAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
599.5 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104	100 mg 1 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BEVIRIMAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
827.9 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104	150 mg 1 times / day multiple, oral dose: 150 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BEVIRIMAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Analyte	Population
62.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104	200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BEVIRIMAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
1.75 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104	25 mg 1 times / day multiple, oral dose: 25 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BEVIRIMAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
56.3 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104	100 mg 1 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BEVIRIMAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
61.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104	150 mg 1 times / day multiple, oral dose: 150 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BEVIRIMAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYPs 22 P-gp 1461	UGT2B7 389 UGT1A3 422 UGT1A8 283 UGT1A4 347 UGT2B17 213 UGT1A10 291 UGT1A6 307 CYPs 33 UGT2B15 203 UGT1A1 418 UGT1A9 380 UGT1A7 236 UGT2B4 249	CYP3A 129

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYPs 28	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/19024627/	no
P-gp 1650	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/19024627/	no
CYP3A 298	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/17596104/	no	likely (expression study) Comment: Urinary 6β-hydroxycortisol/cortisol ratio was not influenced by Bevirimat administration. Sources: https://pubmed.ncbi.nlm.nih.gov/17596104/

Drug as victim

Target	Modality	Activity
UGT1A3 422	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17151190/	major [Km 13 uM]
UGT2B7 389	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17151190/	minor [Km 6 uM]
UGT1A4 347	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17151190/	minor
CYPs 33	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17596104/	no
UGT1A1 418	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17151190/	no
UGT1A10 291	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17151190/	no
UGT1A6 307	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17151190/	no
UGT1A7 236	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17151190/	no
UGT1A8 283	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17151190/	no
UGT1A9 380	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17151190/	no
UGT2B15 203	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17151190/	no
UGT2B17 213	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17151190/	no
UGT2B4 249	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17151190/	no

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P001ZV0	https://www.1pchem.com/search?query=1P001ZV0
AK Scientific	3485AH	https://aksci.com/item_detail.php?cat=3485AH
AstaTech	44148	http://astatechinc.com/CPSResult.php?CRNO=44148
BLD Pharm	BD630448	http://www.bldpharm.com/search/Search.html?keyword=BD630448
BOC Sciences	174022-42-5	http://www.bocsci.com/description.asp?cas=174022-42-5
Biopurify Phytochemicals	BP3086	https://www.phytopurify.com/search.do?a=s&searchtype=3&psize=10&q=BP3086&searchhtmp=simplesearch&t=1
Cayman Chemical	21339	http://www.caymanchem.com/app/template/Product.vm/catalog/21339
Chem Scene	CS-3010	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-3010
Lab Seeker	SC-96858	http://www.labseeker.com/search.php?keywords=SC-96858&category=0
LabSeeker	SC-96858	http://www.labseeker.com/search.php?keywords=SC-96858&category=0
MedChem Express	HY-N0842	https://www.medchemexpress.com/search.html?q=HY-N0842&ft=&fa=&fp=
MolPort	MolPort-006-170-151	https://www.molport.com/shop/molecule-link/MolPort-006-170-151
MuseChem	I002271	https://www.musechem.com/product/I002271.html
Sigma Aldrich	SML2057	http://www.sigmaaldrich.com/catalog/search?term=SML2057&interface=All&N=0&mode=match%20partialmax&lang=en®ion=US&focus=product
TargetMol	T5782	https://www.targetmol.com/search?keyword=T5782
Tetrahedron	TS73398	http://www.thsci.com/search.do?q=TS73398
eMolecules	46301175	https://orderbb.emolecules.com/search/#?query=46301175
mcule	MCULE-8373483440	https://mcule.com/MCULE-8373483440/

PubMed

Title	Date	PubMed
Betulinic acid and dihydrobetulinic acid derivatives as potent anti-HIV agents.	1996 Mar 1	8676334
Anti-AIDS agents--XXVII. Synthesis and anti-HIV activity of betulinic acid and dihydrobetulinic acid derivatives.	1997 Dec	9459011
Anti-AIDS agents. 34. Synthesis and structure-activity relationships of betulin derivatives as anti-HIV agents.	1998 Nov 5	9804704
Anti-AIDS agents 38. Anti-HIV activity of 3-O-acyl ursolic acid derivatives.	2000 Dec	11141100
Synthesis and anti-HIV activity of 3-alkylamido-3-deoxy-betulinic acid derivatives.	2000 Sep	10993248
Synthesis and anti-HIV activity of bi-functional betulinic acid derivatives.	2006 Apr 1	16314103
3-O-(3',3'-dimethysuccinyl) betulinic acid inhibits maturation of the human immunodeficiency virus type 1 Gag precursor assembled in vitro.	2006 Jun	16731910
In vitro resistance to the human immunodeficiency virus type 1 maturation inhibitor PA-457 (Bevirimat).	2006 Nov	16956950
The 3-O-(3',3'-dimethylsuccinyl) derivative of betulinic acid (DSB) inhibits the assembly of virus-like particles in HIV-1 Gag precursor-expressing cells.	2007	18240859
Potent activity of the HIV-1 maturation inhibitor bevirimat in SCID-hu Thy/Liv mice.	2007 Nov 28	18043758
Phase I and II study of the safety, virologic effect, and pharmacokinetics/pharmacodynamics of single-dose 3-o-(3',3'-dimethylsuccinyl)betulinic acid (bevirimat) against human immunodeficiency virus infection.	2007 Oct	17638699
Betulinic acid derivatives as human immunodeficiency virus type 2 (HIV-2) inhibitors.	2009 Dec 10	19526990
Anti-AIDS agents. 78. Design, synthesis, metabolic stability assessment, and antiviral evaluation of novel betulinic acid derivatives as potent anti-human immunodeficiency virus (HIV) agents.	2009 May 28	19388685
A single polymorphism in HIV-1 subtype C SP1 is sufficient to confer natural resistance to the maturation inhibitor bevirimat.	2011 Jul	21502630
Synthesis and biological evaluation of a new derivative of bevirimat that targets the Gag CA-SP1 cleavage site.	2013 Apr	23399723

Patents

Sample Use Guides

In Vivo Use Guide

Four cohorts of six HIV-infected adults, with CD4 counts of >200 and plasma viral loads of 5,000 to 250,000 transcripts/ml and not currently receiving antiretroviral therapy, were randomized to receive a single oral dose of placebo, 75, 150, or 250 mg of bevirimat. The study was a 10-day, randomised, double-blind, placebo-controlled, dose escalation study. A total of 48 healthy male volunteers, aged 19-54 years, took part in the study. Treatment was administered for 10 days in six escalating dose cohorts (n = 8 in each cohort; 6 bevirimat, 2 placebo). The doses of bevirimat given in each successive cohort were 25 mg, 50 mg, 75 mg (with 150 mg loading dose), 100 mg, 150 mg and 200mg. Safety follow-up was performed 28 days after the first dose.

Route of Administration: Oral

In Vitro Use Guide

Bevirimat (PA-457) was shown to be a potent in vitro inhibitor of HIV-1 replication. In assays using patient-derived WT virus isolates, PA-457 exhibited a mean IC50 of 10.3 nM.

Substance Class	Chemical Created by `admin` on `Fri Dec 15 17:20:52 UTC 2023` Edited by `admin` on `Fri Dec 15 17:20:52 UTC 2023`
Record UNII	S125DW66N8
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

BEVIRIMAT

Official Name

English

BEVIRIMAT [MI]

Common Name

English

PA-103001

Code

English

YK-FH312

Common Name

English

bevirimat [INN]

Common Name

English

MPC-4326

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C1660