Relugolix

Details

Stereochemistry	ACHIRAL
Molecular Formula	C29H27F2N7O5S
Molecular Weight	623.63
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CONC(=O)NC1=CC=C(C=C1)C2=C(CN(C)C)C3=C(S2)N(CC4=C(F)C=CC=C4F)C(=O)N(C3=O)C5=NN=C(OC)C=C5

InChI

InChIKey=AOMXMOCNKJTRQP-UHFFFAOYSA-N

InChI=1S/C29H27F2N7O5S/c1-36(2)14-19-24-26(39)38(22-12-13-23(42-3)34-33-22)29(41)37(15-18-20(30)6-5-7-21(18)31)27(24)44-25(19)16-8-10-17(11-9-16)32-28(40)35-43-4/h5-13H,14-15H2,1-4H3,(H2,32,35,40)

HIDE SMILES / InChI

Description

Relugolix (TAK-385) is an orally active nonpeptide gonadotropin-releasing hormone (GnRH) that binds to human GnRH receptors with subnanomolar affinity. Relugolix was demonstrated to act as a classic competitive antagonist of GnRH binding, but the exact molecular mechanism of that antagonism remains unknown. This drug is being developed as a treatment for various sex hormone related disorders. Based on the phase III HERO trial results, relugolix (Orgovyx) received Food and Drug Administration approval for adult patients with advanced prostate cancer. An oral fixed-dose combination of relugolix/estradiol/norethisterone (also known as norethindrone) acetate (Ryeqo®; Myfembree®) has been approved for the management of heavy menstrual bleeding associated with uterine fibroids in the USA and management of moderate to severe symptoms of uterine fibroids in the EU.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Gonadotropin-releasing hormone receptor 41	Antagonist 2,849		0.08 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Prostate cancer 186	Primary	Approved 8,583	ORGOVYX
Menstrual bleeding associated with uterine leiomyomas (fibroids) 1	Primary	Approved 8,583	MYFEMBREE
Pain associated with endometriosis 3	Primary	Approved 8,583	MYFEMBREE

C_max

Value	Dose	Co-administered	Analyte	Population
0.12 ng/mL	1 mg single, oral		RELUGOLIX plasma	Homo sapiens
0.56 ng/mL	5 mg single, oral		RELUGOLIX plasma	Homo sapiens
1.61 ng/mL	10 mg single, oral		RELUGOLIX plasma	Homo sapiens
3.74 ng/mL	20 mg single, oral		RELUGOLIX plasma	Homo sapiens
9.46 ng/mL	40 mg single, oral		RELUGOLIX plasma	Homo sapiens
32.9 ng/mL	80 mg single, oral		RELUGOLIX plasma	Homo sapiens
1.34 ng/mL	10 mg 1 times / day multiple, oral		RELUGOLIX plasma	Homo sapiens
5.06 ng/mL	20 mg 1 times / day multiple, oral		RELUGOLIX plasma	Homo sapiens
19 ng/mL	40 mg 1 times / day multiple, oral		RELUGOLIX plasma	Homo sapiens
2.05 ng/mL	10 mg 1 times / day multiple, oral		RELUGOLIX plasma	Homo sapiens
8.2 ng/mL	20 mg 1 times / day multiple, oral		RELUGOLIX plasma	Homo sapiens
21.8 ng/mL	40 mg 1 times / day multiple, oral		RELUGOLIX plasma	Homo sapiens
19.59 ng/mL	40 mg single, oral	ESTRADIOL	RELUGOLIX plasma	Homo sapiens
8.884 ng/mL	40 mg single, oral	ESTRADIOL	RELUGOLIX plasma	Homo sapiens
12.5 ng/mL	40 mg single, oral		RELUGOLIX plasma	Homo sapiens
9.43 ng/mL	40 mg single, oral		RELUGOLIX plasma	Homo sapiens
14.6 ng/mL	40 mg single, oral		RELUGOLIX plasma	Homo sapiens
11.65 ng/mL	40 mg single, oral		RELUGOLIX plasma	Homo sapiens
20.92 ng/mL	40 mg single, oral		RELUGOLIX plasma	Homo sapiens
14 ng/mL	40 mg single, oral		RELUGOLIX plasma	Homo sapiens
15.4 ng/mL	40 mg single, oral		RELUGOLIX plasma	Homo sapiens
26 ng/mL	40 mg single, oral	ESTRADIOL	RELUGOLIX plasma	Homo sapiens
125 ng/mL	360 mg single, oral		RELUGOLIX plasma	Homo sapiens
46.4 ng/mL	120 mg 1 times / day multiple, oral		RELUGOLIX plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
0.97 ng × h/mL	1 mg single, oral		RELUGOLIX plasma	Homo sapiens
8.44 ng × h/mL	5 mg single, oral		RELUGOLIX plasma	Homo sapiens
18.05 ng × h/mL	10 mg single, oral		RELUGOLIX plasma	Homo sapiens
45.25 ng × h/mL	20 mg single, oral		RELUGOLIX plasma	Homo sapiens
107.67 ng × h/mL	40 mg single, oral		RELUGOLIX plasma	Homo sapiens
293.45 ng × h/mL	80 mg single, oral		RELUGOLIX plasma	Homo sapiens
35.34 ng × h/mL	10 mg 1 times / day multiple, oral		RELUGOLIX plasma	Homo sapiens
18.16 ng × h/mL	20 mg 1 times / day multiple, oral		RELUGOLIX plasma	Homo sapiens
58.65 ng × h/mL	40 mg 1 times / day multiple, oral		RELUGOLIX plasma	Homo sapiens
19.6 ng × h/mL	10 mg 1 times / day multiple, oral		RELUGOLIX plasma	Homo sapiens
58.68 ng × h/mL	20 mg 1 times / day multiple, oral		RELUGOLIX plasma	Homo sapiens
119.04 ng × h/mL	40 mg 1 times / day multiple, oral		RELUGOLIX plasma	Homo sapiens
168.5 ng × h/mL	40 mg single, oral	ESTRADIOL	RELUGOLIX plasma	Homo sapiens
104.6 ng × h/mL	40 mg single, oral	ESTRADIOL	RELUGOLIX plasma	Homo sapiens
123 ng × h/mL	40 mg single, oral		RELUGOLIX plasma	Homo sapiens
84.1 ng × h/mL	40 mg single, oral		RELUGOLIX plasma	Homo sapiens
116 ng × h/mL	40 mg single, oral		RELUGOLIX plasma	Homo sapiens
93.4 ng × h/mL	40 mg single, oral		RELUGOLIX plasma	Homo sapiens
144.6 ng × h/mL	40 mg single, oral		RELUGOLIX plasma	Homo sapiens
109 ng × h/mL	40 mg single, oral		RELUGOLIX plasma	Homo sapiens
163 ng × h/mL	40 mg single, oral		RELUGOLIX plasma	Homo sapiens
198.1 ng × h/mL	40 mg single, oral	ESTRADIOL	RELUGOLIX plasma	Homo sapiens
663 ng × h/mL	360 mg single, oral		RELUGOLIX plasma	Homo sapiens
373 ng × h/mL	120 mg 1 times / day multiple, oral		RELUGOLIX plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
6.6 h	1 mg single, oral	RELUGOLIX plasma	Homo sapiens
14.18 h	5 mg single, oral	RELUGOLIX plasma	Homo sapiens
15.15 h	10 mg single, oral	RELUGOLIX plasma	Homo sapiens
16.23 h	20 mg single, oral	RELUGOLIX plasma	Homo sapiens
16.49 h	40 mg single, oral	RELUGOLIX plasma	Homo sapiens
15.64 h	80 mg single, oral	RELUGOLIX plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
32%			RELUGOLIX plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
360 mg 1 times / day multiple, oral Highest studied dose\|Studied dose	unhealthy, ADULT	Disc. AE: atrioventricular block, cardiac failure...

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AEs

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AE	Significance	Dose	Population
abdominal pain	0.3% Disc. AE	360 mg 1 times / day multiple, oral Highest studied dose\|Studied dose	unhealthy, ADULT
fracture	0.3% Disc. AE	360 mg 1 times / day multiple, oral Highest studied dose\|Studied dose	unhealthy, ADULT
pneumonia	0.3% Disc. AE	360 mg 1 times / day multiple, oral Highest studied dose\|Studied dose	unhealthy, ADULT
atrioventricular block	severe, 0.3% Disc. AE	360 mg 1 times / day multiple, oral Highest studied dose\|Studied dose	unhealthy, ADULT
cardiac failure	severe, 0.3% Disc. AE	360 mg 1 times / day multiple, oral Highest studied dose\|Studied dose	unhealthy, ADULT

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 2,252 substrate 1,946	inhibitor 2,438	inhibitor 2,507	inhibitor 2,217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C8 1,057 P-gp 1,741 BCRP 910 CYP1A2 2,153 BSEP 550 MATE2-K 77 CYP2B6 926 CYP2C19 2,057 OATP1B1 1,079 OATP1B3 961 OAT1 725 OAT3 747 MATE1 415 OCT2 779	P-gp 2,052 BCRP 697 OATP1B1 503 CYP2C8 810 OATP1B3 435	CYP3A 142 CYP1A2 832 CYP2B6 669

Drug as perpetrator

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Target	Modality	Activity
BSEP 554	inhibitor 4,027	no
CYP1A2 2,333	inducer 1,966	no
CYP1A2 2,333	inhibitor 4,027	no
CYP2B6 1,160	inducer 1,966	no
CYP2B6 1,160	inhibitor 4,027	no

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP2C8 810	substrate 4,014	minor
BCRP 697	substrate 4,014	no
OATP1B1 503	substrate 4,014	no
OATP1B3 435	substrate 4,014	no
CYP3A4 1,946	substrate 4,014	yes	yes (co-administration study)

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2,263	inhibitor 2,237

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PubMed

PubMed

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Title	Date	PubMed
Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor.	2011 Jul 28	21657270

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Sample Use Guides

In Vivo Use Guide

Prostate cancer: recommended dosage: a loading dose of 360 mg on the first day of treatment followed by 120 mg taken orally once daily, at approximately the same time each day

Route of Administration: Oral

In Vitro Use Guide

In vitro, in the absence of serum (FBS), TAK-385 bound to human, monkey and rat GnRH receptors with IC50 values of 0.12, 0.15 and 2900 nM, respectively (Study# TAK-385- 00090). Binding affinities decreased by 3-fold in the presence of 40% FBS for all GnRH receptors; nevertheless, TAK-385 bound to the human GnRH receptor with an IC50 value of 0.33 nM

Show entries

Name

Type

Language

Relugolix [INN]

Preferred Name

English

Relugolix

Official Name

English

Myfembree component relugolix

Brand Name

English

Relugolix [WHO-DD]

Common Name

English

Relugolix [JAN]

Common Name

English

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Classification Tree

Code System

Code

Hormone Antagonist

NCI_THESAURUS

C63347

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Code System

Code

Type

Description

DAILYMED

P76B05O5V6

PRIMARY

NCI_THESAURUS

C114498

PRIMARY

INN

9628

PRIMARY

ChEMBL

CHEMBL1800159

PRIMARY

USAN

CD-128

PRIMARY

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ACTIVE MOIETY


					P76B05O5V6

Relugolix

SMILES

InChI

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

PubMed

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator