ELACESTRANT

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C30H38N2O2
Molecular Weight	458.6349
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

[H][C@]1(CCC2=CC(O)=CC=C2C1)C3=C(C=C(OC)C=C3)N(CC)CC4=CC=C(CCNCC)C=C4

InChI

InChIKey=SIFNOOUKXBRGGB-AREMUKBSSA-N

InChI=1S/C30H38N2O2/c1-4-31-17-16-22-6-8-23(9-7-22)21-32(5-2)30-20-28(34-3)14-15-29(30)26-11-10-25-19-27(33)13-12-24(25)18-26/h6-9,12-15,19-20,26,31,33H,4-5,10-11,16-18,21H2,1-3H3/t26-/m1/s1

HIDE SMILES / InChI

Molecular Formula	C30H38N2O2
Molecular Weight	458.6349
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

Elacestrant (ER-306323 or RAD 1901 [6R)-6-(2-(N-(4-(2-(ethylamino)ethyl)benzyl)-N-ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol dihydrochloride]) is an estrogen receptor antagonist that binds to estrogen receptor-alpha (ERα). In ERpositive (ER ) HER2-negative (HER2-) breast cancer cells, elacestrant inhibited 17β-estradiol mediated cell proliferation at concentrations inducing degradation of ERα protein mediated through proteasomal pathway. Elacestrant demonstrated in vitro and in vivo antitumor activity including in ER HER2- breast cancer models resistant to fulvestrant and cyclin-dependent kinase 4/6 inhibitors and those harboring estrogen receptor 1 gene (ESR1) mutations. On January 27, 2023, the Food and Drug Administration (FDA) approved elacestrant (Orserdu, Stemline Therapeutics, Inc.) for postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Estrogen receptor alpha 127	Antagonist 2,778		48.0 nM [Unknown]

Conditions

Condition	Modality	Targets	Highest Phase	Product
ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer	Primary		Approved 8,429	ORSERDU

C_max

Value	Dose	Analyte	Population
119 ng/mL	345 mg single, oral	ELACESTRANT plasma	Homo sapiens
31.5 ng/mL	200 mg single, oral	ELACESTRANT plasma	Homo sapiens
43.5 ng/mL	200 mg 1 times / day multiple, oral	ELACESTRANT plasma	Homo sapiens
543 ng/mL	1000 mg 1 times / day multiple, oral	ELACESTRANT plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
2440 ng × h/mL	345 mg single, oral	ELACESTRANT plasma	Homo sapiens
774 ng × h/mL	200 mg single, oral	ELACESTRANT plasma	Homo sapiens
627 ng × h/mL	200 mg 1 times / day multiple, oral	ELACESTRANT plasma	Homo sapiens
8327 ng × h/mL	1000 mg 1 times / day multiple, oral	ELACESTRANT plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
40 h	345 mg single, oral	ELACESTRANT plasma	Homo sapiens
27.4 h	200 mg single, oral	ELACESTRANT plasma	Homo sapiens
47.3 h	200 mg 1 times / day multiple, oral	ELACESTRANT plasma	Homo sapiens
41.6 h	1000 mg 1 times / day multiple, oral	ELACESTRANT plasma	Homo sapiens

F_unbound

Value	Dose	Analyte	Population
1%	345 mg single, oral	ELACESTRANT plasma	Homo sapiens
1%	200 mg single, oral	ELACESTRANT plasma	Homo sapiens
1%	200 mg 1 times / day multiple, oral	ELACESTRANT plasma	Homo sapiens
1%	1000 mg 1 times / day multiple, oral	ELACESTRANT plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
863 mg 1 times / day multiple, oral Highest studied dose	healthy, ADULT	Disc. AE: Gastrointestinal disorder...
400 mg 1 times / day multiple, oral Studied dose	unhealthy, ADULT	Disc. AE: Musculoskeletal pain, Nausea... Other AEs: Musculoskeletal pain, Nausea...

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AEs

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AE	Significance	Dose	Population
Gastrointestinal disorder	grade 1-3 Disc. AE	863 mg 1 times / day multiple, oral Highest studied dose	healthy, ADULT
Increased ALT	1.3% Disc. AE	400 mg 1 times / day multiple, oral Studied dose	unhealthy, ADULT
Nausea	1.3% Disc. AE	400 mg 1 times / day multiple, oral Studied dose	unhealthy, ADULT
Nausea	1.7%	400 mg 1 times / day multiple, oral Studied dose	unhealthy, ADULT
Musculoskeletal pain	1.7% Disc. AE	400 mg 1 times / day multiple, oral Studied dose	unhealthy, ADULT

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737	substrate 1,037 inhibitor 1,767 inducer 389	inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2E1 882 CYP2A6 707 OAT3 642 CYP1A2 1,524 OAT1 599 CYP2C19 1,478 CYP2C8 911 CYP3A 214 MATE1 306 CYP2B6 810 OATP1B1 788 OCT2 647 MATE2-K 9 OCT1 512 OATP1B3 706 P-gp 1,461 BCRP 699	CYP2A6 543	CYP2B6 547 CYP1A2 701 CYP2C19 293 CYP2A6 79 CYP3A 129

Drug as perpetrator

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Target	Modality	Activity
CYP1A2 1,692	inducer 1,573	no
CYP1A2 1,692	inhibitor 3,277	no
CYP2A6 739	inducer 1,573	no
CYP2A6 739	inhibitor 3,277	no
CYP2B6 1,001	inducer 1,573	no

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP3A4 1,737	substrate 3,367	major
CYP2A6 543	substrate 3,367	minor
CYP2C9 1,037	substrate 3,367	minor	yes (co-administration study)

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

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PubMed

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Title	Date	PubMed
Latest generation estrogen receptor degraders for the treatment of hormone receptor-positive breast cancer.	2022 Jun	34694932

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Patents

Sample Use Guides

In Vivo Use Guide

The recommended dosage of ORSERDU is one 345 mg tablet taken orally, once daily, with food

Route of Administration: Oral

In Vitro Use Guide

In competitive receptor binding assays, the IC50 for RAD1901 on ERα was 48 versus 870 nmol/l for ERβ. For the E2 control, the IC50 values for ERα and ERβ were 0.4 and 0.3 nmol/l, respectively.

Substance Class	Chemical
Record UNII	FM6A2627A8
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

ELACESTRANT

Official Name

English

RAD1901

Code

English

ER-306323

Code

English

RAD-1901

Code

English

(2R)-2-(2-(ETHYL-((4-(2-(ETHYLAMINO)ETHYL)PHENYL)METHYL)AMINO)-4-METHOXY-PHENYL)TETRALIN-6-OL

Systematic Name

English

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Classification Tree

Code System

Code

Antiestrogen

NCI_THESAURUS

C1821

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Code System

Code

Type

Description

USAN

GH-120

PRIMARY

CLINICAL_TRIALS.GOV

RAD-1901

PRIMARY

Study to Evaluate the Safety and Efficacy of RAD1901 in Postmenopausal Women With Moderate to Severe Vasomotor Symptoms

NCI_THESAURUS

C120211

PRIMARY

MANUFACTURER PRODUCT INFORMATION

RAD-1901

PRIMARY

Description: RAD1901 is an orally available, selective estrogen receptor degrader (SERD) and selective estrogen receptor modulator (SERM), with potential antineoplastic and estrogen-like activities. Upon oral administration of higher doses of RAD1901, this agent acts as a SERD, which binds to the estrogen receptor (ER) and induces a conformational change that results in the degradation of the receptor. This may inhibit the growth and survival of ER-expressing cancer cells. At lower doses of this agent, RAD1901 acts as a SERM and has estrogen-like effects in certain tissues, which can both reduce hot flashes and protect against bone loss. In addition, RAD1901 is able to cross the blood-brain barrier (BBB). (last updated: 5/19/2016).Synonym: RAD1901, RAD-1901, RAD 1901, RAD1901 HCl salt.

ChEMBL

CHEMBL3545015

PRIMARY

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Related Record

Type

Details


					SIDP85PFD6

ESTROGEN RECEPTOR

TARGET->INHIBITOR, RECEPTOR DEGRADER

Amount:


					8NZT0PR8AL

ELACESTRANT HYDROCHLORIDE

SALT/SOLVATE -> PARENT

Amount:

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Related Record

Type

Details


					FM6A2627A8

ELACESTRANT

ACTIVE MOIETY

Comments:

Class: Osteoporosis therapy, Small molecule, Tetra-hydro-naphthalene; Mechanism of Action: Selective estrogen receptor degraders, Selective estrogen receptor modulator; Highest Development Phases: Phase II for Vasomotor symptoms, Phase I for Breast cancer; Most Recent Events: 08 Feb 2016 Radius, in collaboration with Novartis, plan a clinical trial for RAD 1901 in combination with LEE 011 in the treatment of Breast cancer, 27 Jan 2016 Radius Health and Novartis enter into a clinical collaboration to evaluate combination regimens, RAD 1901 and ricociclib, for the treatment of Breast cancer, 01 Dec 2015 Phase-II clinical trials in Vasomotor symptoms in USA (PO) (NCT02653417)

Amount:

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SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator