Mitapivat Sulfate

Details

Stereochemistry	ACHIRAL
Molecular Formula	2C24H26N4O3S.3H2O.H2O4S
Molecular Weight	1053.231
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

O.O.O.OS(O)(=O)=O.O=C(N1CCN(CC2CC2)CC1)C3=CC=C(NS(=O)(=O)C4=C5N=CC=CC5=CC=C4)C=C3.O=C(N6CCN(CC7CC7)CC6)C8=CC=C(NS(=O)(=O)C9=C%10N=CC=CC%10=CC=C9)C=C8

InChI

InChIKey=DMRIPASJCJRBMV-UHFFFAOYSA-N

InChI=1S/2C24H26N4O3S.H2O4S.3H2O/c2*29-24(28-15-13-27(14-16-28)17-18-6-7-18)20-8-10-21(11-9-20)26-32(30,31)22-5-1-3-19-4-2-12-25-23(19)22;1-5(2,3)4;;;/h2*1-5,8-12,18,26H,6-7,13-17H2;(H2,1,2,3,4);3*1H2

HIDE SMILES / InChI

Description

Mitapivat (AG-348; PKM2 activator 1020) is a novel, first-in-class oral small molecule allosteric activator of the pyruvate kinase enzyme. Mitapivat has been shown to significantly upregulate both wild-type and numerous mutant forms of erythrocyte pyruvate kinase (PKR), increasing adenosine triphosphate (ATP) production and reducing levels of 2,3-diphosphoglycerate. Given this mechanism, mitapivat has been evaluated in clinical trials in a wide range of hereditary hemolytic anemias, including pyruvate kinase deficiency (PKD), sickle cell disease, and the thalassemias. Mitapivat was approved for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency in the United States in February 2022, and in the European Union in November 2022.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Pyruvate kinase PKLR 3	Positive Allosteric Modulator 186
Pyruvate kinase isozymes M1/M2 12	Activator 1,447

Conditions

Condition	Modality	Targets	Highest Phase	Product
Hemolytic anemia due to pyruvate kinase deficiency 3	Primary		Approved 8,583	PYRUKYND

C_max

Value	Dose	Analyte	Population
101.2 ng/mL	5 mg 2 times / day steady-state, oral	MITAPIVAT plasma	Homo sapiens
389.9 ng/mL	20 mg 2 times / day steady-state, oral	MITAPIVAT plasma	Homo sapiens
935.2 ng/mL	50 mg 2 times / day steady-state, oral	MITAPIVAT plasma	Homo sapiens
76 ng/mL	5 mg single, oral	MITAPIVAT plasma	Homo sapiens
1005 ng/mL	50 mg single, oral	MITAPIVAT plasma	Homo sapiens
4425 ng/mL	200 mg single, oral	MITAPIVAT plasma	Homo sapiens
248 ng/mL	15 mg 2 times / day multiple, oral	MITAPIVAT plasma	Homo sapiens
255 ng/mL	15 mg 2 times / day multiple, oral	MITAPIVAT plasma	Homo sapiens
1287 ng/mL	60 mg 2 times / day multiple, oral	MITAPIVAT plasma	Homo sapiens
1322 ng/mL	60 mg 2 times / day multiple, oral	MITAPIVAT plasma	Homo sapiens
2806 ng/mL	120 mg 1 times / day multiple, oral	MITAPIVAT plasma	Homo sapiens
2094 ng/mL	120 mg 1 times / day multiple, oral	MITAPIVAT plasma	Homo sapiens
1033 ng/mL	50 mg 2 times / day multiple, oral	MITAPIVAT plasma	Homo sapiens
938 ng/mL	50 mg 2 times / day multiple, oral	MITAPIVAT plasma	Homo sapiens
131 ng/mL	5 mg 2 times / day steady-state, oral	MITAPIVAT plasma	Homo sapiens
499 ng/mL	20 mg 2 times / day steady-state, oral	MITAPIVAT plasma	Homo sapiens
1178 ng/mL	50 mg 2 times / day steady-state, oral	MITAPIVAT plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
450.4 ng × h/mL	5 mg 2 times / day steady-state, oral	MITAPIVAT plasma	Homo sapiens
1623.8 ng × h/mL	20 mg 2 times / day steady-state, oral	MITAPIVAT plasma	Homo sapiens
3591.4 ng × h/mL	50 mg 2 times / day steady-state, oral	MITAPIVAT plasma	Homo sapiens
304 ng × h/mL	5 mg single, oral	MITAPIVAT plasma	Homo sapiens
4007 ng × h/mL	50 mg single, oral	MITAPIVAT plasma	Homo sapiens
15642 ng × h/mL	200 mg single, oral	MITAPIVAT plasma	Homo sapiens
778 ng × h/mL	15 mg 2 times / day multiple, oral	MITAPIVAT plasma	Homo sapiens
938 ng × h/mL	15 mg 2 times / day multiple, oral	MITAPIVAT plasma	Homo sapiens
3279 ng × h/mL	60 mg 2 times / day multiple, oral	MITAPIVAT plasma	Homo sapiens
3358 ng × h/mL	60 mg 2 times / day multiple, oral	MITAPIVAT plasma	Homo sapiens
10034 ng × h/mL	120 mg 1 times / day multiple, oral	MITAPIVAT plasma	Homo sapiens
8461 ng × h/mL	120 mg 1 times / day multiple, oral	MITAPIVAT plasma	Homo sapiens
3162 ng × h/mL	50 mg 2 times / day multiple, oral	MITAPIVAT plasma	Homo sapiens
2628 ng × h/mL	50 mg 2 times / day multiple, oral	MITAPIVAT plasma	Homo sapiens
440 ng × h/mL	5 mg 2 times / day steady-state, oral	MITAPIVAT plasma	Homo sapiens
1582 ng × h/mL	20 mg 2 times / day steady-state, oral	MITAPIVAT plasma	Homo sapiens
3482 ng × h/mL	50 mg 2 times / day steady-state, oral	MITAPIVAT plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
5 h	5 mg 2 times / day steady-state, oral	MITAPIVAT plasma	Homo sapiens
5 h	20 mg 2 times / day steady-state, oral	MITAPIVAT plasma	Homo sapiens
5 h	50 mg 2 times / day steady-state, oral	MITAPIVAT plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
2.3%			MITAPIVAT plasma	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
2500 mg single, oral Highest studied dose	healthy, ADULT
50 mg 2 times / day steady, oral Recommended\|Studied dose	unhealthy, ADULT	Disc. AE: insomnia, headache...
20 mg 2 times / day multiple, oral Studied dose		Disc. AE: Joint swelling, Back pain...

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AEs

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AE	Significance	Dose	Population
headache	15% Disc. AE	50 mg 2 times / day steady, oral Recommended\|Studied dose	unhealthy, ADULT
headache	15% Disc. AE	50 mg 2 times / day steady, oral Recommended\|Studied dose	unhealthy, ADULT
insomnia	15% Disc. AE	50 mg 2 times / day steady, oral Recommended\|Studied dose	unhealthy, ADULT
insomnia	15% Disc. AE	50 mg 2 times / day steady, oral Recommended\|Studied dose	unhealthy, ADULT
headache	19% Disc. AE	50 mg 2 times / day steady, oral Recommended\|Studied dose	unhealthy, ADULT

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 1,087 substrate 1,946	inducer 440	substrate 1,388	inhibitor 2,217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OAT3 747 BSEP 550 OATP1B3 961 P-gp 1,741 BCRP 910 OCT2 779 MATE1 415	CYP1A2 1,197 OATP1B3 435 OATP1B1 503 BCRP 697 CYP3A5 446 P-gp 2,052 UGT1A1 479	CYP2B6 669 CYP3A5 92 CYP2C8 198 UGT1A1 78 CYP2C19 329

Drug as perpetrator

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Target	Modality	Activity
BCRP 985	inhibitor 4,027	no
OATP1B3 970	inhibitor 4,027	no
OAT3 749	inhibitor 4,027	yes [IC50 12.1 uM]
P-gp 1,932	inhibitor 4,027	yes [IC50 12.8 uM]
BSEP 554	inhibitor 4,027	yes [IC50 22 uM]

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Drug as victim

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Target	Modality	Activity
CYP1A2 1,197	substrate 4,014	minor
CYP2D6 1,388	substrate 4,014	minor
BCRP 697	substrate 4,014	no
OATP1B1 503	substrate 4,014	no
OATP1B3 435	substrate 4,014	no

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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

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Title	Date	PubMed
Mitapivat, a novel pyruvate kinase activator, for the treatment of hereditary hemolytic anemias.	2021	34987744
An evaluation of mitapivat for the treatment of hemolytic anemia in adults with pyruvate kinase deficiency.	2022 Oct	36124781

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Patents

Sample Use Guides

In Vivo Use Guide

The starting dosage for PYRUKYND is 5 mg orally twice daily. To gradually increase hemoglobin (Hb), titrate PYRUKYND from 5 mg twice daily to 20 mg twice daily, and then to the maximum recommended dose of 50 mg twice daily, with these dose increases occurring every 4 weeks

Route of Administration: Oral

In Vitro Use Guide

In human red blood cells, mitapivat activates PKR with AC50 and AC90 for PKR activation of 0.0619±0.0346 uM and 1.002±1.109 uM, respectively. The average maximum percent PKR activation was 274%±56%. It was demonstrated that while the WT PKR was activated by mitapivat with AC50 0.013 uM the 10 mutant PKR isoforms evaluated were activated with AC50 values ranged approximately 0.009 to 0.059 uM.

Show entries

Name

Type

Language

Mitapivat Sulfate

Official Name

English

PYRUKYND

Preferred Name

English

Mitapivat hemisulfate sesquihydrate

Common Name

English

AG-348 SULFATE HYDRATE

Code

English

8-Quinolinesulfonamide, N-[4-[[4-(cyclopropylmethyl)-1-piperazinyl]carbonyl]phenyl]-, sulfate, hydrate (2:1:3)

Systematic Name

English

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Classification Tree

Code System

Code

Designated/Approved

FDA ORPHAN DRUG

442814

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Code System

Code

Type

Description

SMS_ID

100000183179

PRIMARY

PUBCHEM

134693700

PRIMARY

FDA UNII

N4JTA67V3O

PRIMARY

NCI_THESAURUS

C174739

PRIMARY

CAS

2151847-10-6

PRIMARY

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ACTIVE MOIETY


					2WTV10SIKH

MITAPIVAT

SUBSTANCE RECORD


					N4JTA67V3O

Mitapivat Sulfate

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