TROFINETIDE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C13H21N3O6
Molecular Weight	315.3223
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

C[C@]1(CCCN1C(=O)CN)C(=O)N[C@@H](CCC(O)=O)C(O)=O

InChI

InChIKey=BUSXWGRAOZQTEY-SDBXPKJASA-N

InChI=1S/C13H21N3O6/c1-13(5-2-6-16(13)9(17)7-14)12(22)15-8(11(20)21)3-4-10(18)19/h8H,2-7,14H2,1H3,(H,15,22)(H,18,19)(H,20,21)/t8-,13-/m0/s1

HIDE SMILES / InChI

Molecular Formula	C13H21N3O6
Molecular Weight	315.3223
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	2 / 2
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217026s000lbl.pdf|

Trofinetide (NNZ 2566), a proprietary small molecule analogue of glycine-proline-glutamate [Glypromate®], is being developed by Neuren Pharmaceuticals and Acadia Pharmaceuticals for the treatment of brain injuries, fragile X syndrome, Rett syndrome. Trofinetide is a synthetic analogue of a naturally occurring neurotrophic peptide derived from IGF-1, a growth factor produced by brain cells. In animal models, trofinetide exhibits a wide range of important effects including inhibiting neuroinflammation, normalizing the role of microglia and correcting deficits in synaptic function. Trofinetide was approved in March 2023 in the USA for the treatment of Rett syndrome in adult and pediatric patients 2 years of age and older.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Glutamate NMDA receptor; Grin1/Grin2b 5 Target ID: CHEMBL2096666 Sources: https://pubmed.ncbi.nlm.nih.gov/16650992/	Antagonist 2849	7960.0 nM [Ki]
Glutamate NMDA receptor; Grin1/Grin2a 5 Target ID: CHEMBL2096680 Sources: https://pubmed.ncbi.nlm.nih.gov/16650992/	Antagonist 2849	7960.0 nM [Ki]
Glutamate NMDA receptor; Grin1/Grin2c 5 Target ID: CHEMBL2096911 Sources: https://pubmed.ncbi.nlm.nih.gov/16650992/	Antagonist 2849	7960.0 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Rett syndrome 3 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217026s000lbl.pdf	Primary		Approved 8583	DAYBUE Approved Use DAYBUE is indicated for the treatment of Rett syndrome in adults and pediatric patients 2 years of age and older. Launch Date 2023

C_max

Value	Dose	Co-administered	Analyte	Population
150 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/35622206/	12 g single, oral dose: 12 g route of administration: Oral experiment type: SINGLE co-administered:		TROFINETIDE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
118 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/35622206/	12 g single, oral dose: 12 g route of administration: Oral experiment type: SINGLE co-administered:		TROFINETIDE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED

AUC

Value	Dose	Co-administered	Analyte	Population
806 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/35622206/	12 g single, oral dose: 12 g route of administration: Oral experiment type: SINGLE co-administered:		TROFINETIDE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
748 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/35622206/	12 g single, oral dose: 12 g route of administration: Oral experiment type: SINGLE co-administered:		TROFINETIDE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED

T_1/2

Value	Dose	Co-administered	Analyte	Population
13.5 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/35622206/	12 g single, oral dose: 12 g route of administration: Oral experiment type: SINGLE co-administered:		TROFINETIDE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
14.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/35622206/	12 g single, oral dose: 12 g route of administration: Oral experiment type: SINGLE co-administered:		TROFINETIDE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED

F_unbound

Value	Dose	Co-administered	Analyte	Population
94% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217026s000lbl.pdf	unknown, unknown		TROFINETIDE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 2252 inducer 1087 substrate 1946	inhibitor 2438 substrate 1193	inhibitor 2507 substrate 1388	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OAT1 725 UGT1A9 148 CYP2B6 926 CYP1A2 2153 OATP1B1 1079 MATE2-K 77 P-gp 1741 OAT3 747 CYP2C8 1057 MATE1 415 BSEP 550 BCRP 910 OATP1B3 961 CYP2C19 2057 CYP3A5 136 UGT2B7 197 UGT1A1 246 UGT1A4 98 UGT2B15 84 UGT2B17 31 OCT2 779 UGT1A3 89 UGT1A6 136	BSEP 63 OAT1 395 OATP1B3 435 BCRP 697 OAT3 391 P-gp 2052 OCT2 434 OATP1B1 503 MATE1 182 MATE2-K 33 CYP1A2 1197 CYP2B6 776 CYP2C8 810 CYP2C19 1119 MATE2 98	CYP2B6 669 CYP1A2 832

Drug as perpetrator

Target	Modality	Activity
CYP1A2 2333	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000PharmR.pdf \| https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf#page=28 Page: 23.0	no [IC50 10000 uM]
CYP2C19 2141	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000PharmR.pdf \| https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf#page=28 Page: 23.0	no [IC50 10000 uM]
CYP2D6 2546	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000PharmR.pdf \| https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf#page=28 Page: 23.0	no [IC50 12000 uM]
CYP3A4 2633	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000PharmR.pdf \| https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf#page=28 Page: 23.0	no [IC50 13000 uM]
CYP3A5 201	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000PharmR.pdf \| https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf#page=28 Page: 23.0	no [IC50 13000 uM]
CYP2B6 1160	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000PharmR.pdf \| https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf#page=28 Page: 23.0	no [IC50 18000 uM]
CYP2C8 1117	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000PharmR.pdf \| https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf#page=28 Page: 23.0	no [IC50 4800 uM]
CYP2C9 2497	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 13 \| 29	no [IC50 >25000 uM]
UGT1A1 303	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 30.0	no [IC50 >25000 uM]
UGT1A3 99	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 30.0	no [IC50 >25000 uM]
UGT1A4 100	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 30.0	no [IC50 >25000 uM]
UGT1A6 171	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 30.0	no [IC50 >25000 uM]
UGT2B17 33	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 30.0	no [IC50 >25000 uM]
OAT3 749	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 9.0	no
OAT1 730	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 9 \| 30	unlikely [IC50 10900 uM]
BCRP 985	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 9 \| 30	unlikely [IC50 13500 uM]
P-gp 1932	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 9 \| 31	unlikely [IC50 17200 uM]
OCT2 782	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 9 \| 30	unlikely [IC50 3640 uM]
MATE1 416	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 9 \| 30	unlikely [IC50 3680 uM]
BSEP 554	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 9 \| 30	unlikely [IC50 8970 uM]
MATE2-K 77	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 9.0	unlikely [IC50 951 uM]
UGT2B7 210	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 14 \| 23 \| 30	yes [IC50 10000 uM]
OATP1B3 970	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 6 \| 9 \| 24 \| 31	yes [IC50 11500 uM]
OATP1B1 1095	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 6 \| 9 \| 24 \| 31	yes [IC50 11700 uM]
UGT1A9 155	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 14 \| 23 \| 30	yes [IC50 12000 uM]
UGT2B15 84	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 14 \| 23 \| 30	yes [IC50 23000 uM]
CYP1A2 2333	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000PharmR.pdf Page: 23.0	yes
CYP2B6 1160	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000PharmR.pdf Page: 23.0	yes
CYP3A4 2633	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000PharmR.pdf Page: 23.0	yes

Drug as victim

Target	Modality	Activity
CYP1A2 1197	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 7 \| 8 \| 22 \| 28	minor
CYP2B6 776	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 7 \| 8 \| 22 \| 28	minor
CYP2C19 1119	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 7 \| 8 \| 22 \| 28	minor
CYP2C8 810	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 7 \| 8 \| 22 \| 28	minor
CYP2C9 1193	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 7 \| 8 \| 22 \| 28	minor
CYP2D6 1388	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 7 \| 8 \| 22 \| 28	minor
CYP3A4 1946	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 7 \| 8 \| 22 \| 28	minor
BCRP 697	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 13 \| 30	no
BSEP 63	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 13 \| 30	no
MATE1 182	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 13 \| 30	no
MATE2 98	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 30.0	no
MATE2-K 33	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 13 \| 30	no
OAT1 395	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 13 \| 30	no
OAT3 391	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 13 \| 30	no
OATP1B3 435	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 13 \| 30	no
OCT2 434	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 13 \| 30	no
P-gp 2052	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 13 \| 30	no
OATP1B1 503	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000ClinPharmR.pdf Page: 13 \| 30	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217026Orig1s000PharmR.pdf Page: 9 \| 19

PubMed

Title	Date	PubMed
Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome.	2019-04-16	30918097
A Double-Blind, Randomized, Placebo-Controlled Clinical Study of Trofinetide in the Treatment of Rett Syndrome.	2017-11	28964591
Progress in Rett Syndrome: from discovery to clinical trials.	2016-09	27491553

Patents

Sample Use Guides

In Vivo Use Guide

Rett syndrome: Recommended dosage is twice daily, morning and evening, according to patient weight. 9 kg to less than 12 kg: 5,000 mg twice daily; 12 kg o less than 20 kg: 6,000 mg twice daily; 20 kg to less than 35 kg: 8,000 mg twice daily; 35 kg to less than 50 kg: 10,000 mg twice daily; 50 kg or more: 12,000 mg twice daily.

Route of Administration: Oral

In Vitro Use Guide

Trofinetide displaced L[3H]glutamate from GluR in rat brain synaptic membrane with Ki 7960.0 nM.

Substance Class	Chemical Created by `admin` on `Mon Mar 31 18:39:40 GMT 2025` Edited by `admin` on `Mon Mar 31 18:39:40 GMT 2025`
Record UNII	Z2ME8F52QL
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

trofinetide [INN]

Preferred Name

English

TROFINETIDE

Official Name

English

NNZ-2566

Code

English

TROFINETIDE [USAN]

Common Name

English

ACP-2566

Code

English

glycyl-2-methyl-L-prolyl-L-glutamic acid

Systematic Name

English

DAYBUE

Brand Name

English

L-Glutamic acid, glycyl-2-methyl-L-prolyl-

Common Name

English

Trofinetide [WHO-DD]

Common Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

409013