SETMELANOTIDE ACETATE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C49H68N18O9S2.3C2H4O2
Molecular Weight	1297.465
Optical Activity	UNSPECIFIED
Defined Stereocenters	8 / 8
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CC(O)=O.CC(O)=O.CC(O)=O.C[C@H]1NC(=O)[C@H](CSSC[C@H](NC(=O)[C@H](CC2=CNC3=CC=CC=C23)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](CC4=CC=CC=C4)NC(=O)[C@H](CC5=CN=CN5)NC1=O)C(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O

InChI

InChIKey=PILXXDANZBQUJH-AKVBKPKISA-N

InChI=1S/C49H68N18O9S2.3C2H4O2/c1-26-41(70)63-37(20-30-22-55-25-59-30)46(75)64-35(18-28-10-4-3-5-11-28)44(73)62-34(15-9-17-57-49(53)54)43(72)65-36(19-29-21-58-32-13-7-6-12-31(29)32)45(74)66-38(40(50)69)23-77-78-24-39(47(76)60-26)67-42(71)33(61-27(2)68)14-8-16-56-48(51)52;3*1-2(3)4/h3-7,10-13,21-22,25-26,33-39,58H,8-9,14-20,23-24H2,1-2H3,(H2,50,69)(H,55,59)(H,60,76)(H,61,68)(H,62,73)(H,63,70)(H,64,75)(H,65,72)(H,66,74)(H,67,71)(H4,51,52,56)(H4,53,54,57);3*1H3,(H,3,4)/t26-,33+,34+,35-,36+,37+,38+,39+;;;/m1.../s1

HIDE SMILES / InChI

Molecular Formula	C2H4O2
Molecular Weight	60.052
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Molecular Formula	C49H68N18O9S2
Molecular Weight	1117.309
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	8 / 8
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

Setmelanotide (IMCIVREE™) is a melanocortin-4 (MC4) receptor agonist developed by Rhythm Pharmaceuticals (Rhythm) for the treatment of ultrarare genetic disorders of obesity. Setmelanotide was approved on 27 November 2020 in the USA as a subcutaneous (SC) injectable formulation for chronic weight management in adult and pediatric patients 6 years of age and older with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by genetic testing demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS). Rhythm are also developing the drug for the treatment of obesity associated with other rare genetic disorders including Bardet–Biedl Syndrome, Alström Syndrome, POMC and other MC4R pathway heterozygous defciency obesities, and POMC epigenetic disorders.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Melanocortin receptor 4 5	Agonist 2,678		0.27 nM [EC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by genetic testing demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS).	Primary		Approved 8,429	IMCIVREE

C_max

Value	Dose	Analyte	Population
6.65 ng/mL	0.5 mg 1 times / day steady-state, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
10.4 ng/mL	1 mg 1 times / day steady-state, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
17.5 ng/mL	1.5 mg 1 times / day steady-state, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
25.1 ng/mL	2 mg 1 times / day steady-state, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
32.8 ng/mL	2.5 mg 1 times / day steady-state, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
38 ng/mL	2.5 mg 1 times / day steady-state, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
25.4 ng/mL	0.0215 mg/kg single, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
14.2 ng/mL	0.75 mg 2 times / day steady-state, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
23 ng/mL	1.5 mg 1 times / day steady-state, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
27.5 ng/mL	2 mg 1 times / day steady-state, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
19.7 ng/mL	2 mg single, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
24.8 ng/mL	1.5 mg single, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
17.5 ng/mL	2 mg single, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
6.47 ng/mL	0.5 mg 1 times / day unknown, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
11.5 ng/mL	1 mg 1 times / day unknown, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
22.4 ng/mL	1.5 mg 1 times / day unknown, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
24.5 ng/mL	2 mg 1 times / day unknown, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
24.4 ng/mL	2.5 mg 1 times / day unknown, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
7.21 ng/mL	0.5 mg 1 times / day unknown, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
10.4 ng/mL	1 mg 1 times / day unknown, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
17 ng/mL	1.5 mg 1 times / day unknown, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
23.9 ng/mL	2 mg 1 times / day unknown, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
31.1 ng/mL	2.5 mg 1 times / day unknown, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
38.9 ng/mL	3 mg 1 times / day unknown, subcutaneous	SETMELANOTIDE plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
35.8 ng × h/mL	0.5 mg 1 times / day steady-state, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
59.3 ng × h/mL	1 mg 1 times / day steady-state, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
106 ng × h/mL	1.5 mg 1 times / day steady-state, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
146 ng × h/mL	2 mg 1 times / day steady-state, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
188 ng × h/mL	2.5 mg 1 times / day steady-state, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
207 ng × h/mL	2.5 mg 1 times / day steady-state, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
243 ng × h/mL	0.75 mg 2 times / day steady-state, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
271 ng × h/mL	1.5 mg 1 times / day steady-state, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
347 ng × h/mL	2 mg 1 times / day steady-state, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
253 ng × h/mL	2 mg single, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
111 ng × h/mL	1.5 mg single, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
36.2 ng × h/mL	2 mg single, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
38.3 ng × h/mL	0.5 mg 1 times / day unknown, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
74.2 ng × h/mL	1 mg 1 times / day unknown, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
147 ng × h/mL	1.5 mg 1 times / day unknown, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
159 ng × h/mL	2 mg 1 times / day unknown, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
180 ng × h/mL	2.5 mg 1 times / day unknown, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
56.2 ng × h/mL	0.5 mg 1 times / day unknown, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
79.1 ng × h/mL	1 mg 1 times / day unknown, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
130 ng × h/mL	1.5 mg 1 times / day unknown, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
178 ng × h/mL	2 mg 1 times / day unknown, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
260 ng × h/mL	2.5 mg 1 times / day unknown, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
383 ng × h/mL	3 mg 1 times / day unknown, subcutaneous	SETMELANOTIDE plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
8.98 h	0.0215 mg/kg single, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
5.91 h	0.75 mg 2 times / day steady-state, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
7.55 h	1.5 mg 1 times / day steady-state, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
7.73 h	2 mg 1 times / day steady-state, subcutaneous	SETMELANOTIDE plasma	Homo sapiens
6.18 h	2 mg single, subcutaneous	SETMELANOTIDE plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
20.9%			SETMELANOTIDE plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
3 mg 1 times / day multiple, subcutaneous Highest studied dose	unhealthy, CHILD\|ADOLESCENT\|ADULT	Disc. AE: Depression, Upper respiratory tract infection... Other AEs: Spontaneous penile erection, Suicidal ideation...

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AEs

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AE	Significance	Dose	Population
Adrenal insufficiency		3 mg 1 times / day multiple, subcutaneous Highest studied dose	unhealthy, CHILD\|ADOLESCENT\|ADULT
Hyperhidrosis		3 mg 1 times / day multiple, subcutaneous Highest studied dose	unhealthy, CHILD\|ADOLESCENT\|ADULT
Pleuritis		3 mg 1 times / day multiple, subcutaneous Highest studied dose	unhealthy, CHILD\|ADOLESCENT\|ADULT
Pneumonia		3 mg 1 times / day multiple, subcutaneous Highest studied dose	unhealthy, CHILD\|ADOLESCENT\|ADULT
Panic attack	1	3 mg 1 times / day multiple, subcutaneous Highest studied dose	unhealthy, CHILD\|ADOLESCENT\|ADULT

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 781 inhibitor 1,587	inhibitor 1,767	inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OATP1B1 788 OATP1B3 706 CYP2C19 1,478 CYP1A2 1,524 CYP2B6 810 CYP2A6 707 CYP2C8 911 P-gp 1,461 BCRP 699 OCT2 647 OAT1 599 MATE1 306 OAT3 642 MATE2K	OCT2 355 OATP1B3 350 OATP1B1 406 MATE1 135 P-gp 1,537 OAT1 326 MATE2K BCRP 561 OAT3 339	CYP1A2 701 CYP2B6 547

Drug as perpetrator

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Target	Modality	Activity
CYP1A2 1,692	inhibitor 3,277	no [IC50 >1000 uM]
CYP2C19 1,553	inhibitor 3,277	no [IC50 >1000 uM]
CYP2C9 1,819	inhibitor 3,277	no [IC50 >1000 uM]
CYP2D6 1,891	inhibitor 3,277	no [IC50 >1000 uM]
BCRP 773	inhibitor 3,277	no

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Drug as victim

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Target	Modality	Activity
BCRP 561	substrate 3,367	no
MATE1 135	substrate 3,367	no
MATE2K	substrate 3,367	no
OAT1 326	substrate 3,367	no
OAT3 339	substrate 3,367	no

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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

PubMed

Title	Date	PubMed
No data available in table

Sample Use Guides

In Vivo Use Guide

Obesity due to deficiency of POMC, PCSK1, or LEPR: 2 mg (0.2 mL) injected subcutaneously once daily for 2 weeks.

Route of Administration: Other

In Vitro Use Guide

Setmelanotide (RM-493) binds human MC4R with Ki value of 0.71 nM in radioligand binding assay and activated MC4R with EC50 value of 1.5 nM in intracellular cAMP production assay.

Substance Class	Chemical
Record UNII	224I1W20I7
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

SETMELANOTIDE ACETATE

Common Name

English

SETMELANOTIDE ACETATE [ORANGE BOOK]

Common Name

English

Setmelanotide acetate [WHO-DD]

Common Name

English

IMCIVREE

Brand Name

English

RM-493 ACETATE

Code

English

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Code System

Code

Type

Description

FDA UNII

224I1W20I7

PRIMARY

CAS

1504602-49-6

NON-SPECIFIC STOICHIOMETRY

RXCUI

2469248

PRIMARY

PUBCHEM

155491122

PRIMARY

PUBCHEM

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Type

Details


					N7T15V1FUY

SETMELANOTIDE

PARENT -> SALT/SOLVATE

Amount:

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Type

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					N7T15V1FUY

SETMELANOTIDE

ACTIVE MOIETY

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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

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator