PF-06282999

Investigational

Details

Stereochemistry	ACHIRAL
Molecular Formula	C13H12ClN3O3S
Molecular Weight	325.771
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

COC1=CC=C(Cl)C=C1C2=CC(=O)NC(=S)N2CC(N)=O

InChI

InChIKey=ICYNYWFGIDGBRD-UHFFFAOYSA-N

InChI=1S/C13H12ClN3O3S/c1-20-10-3-2-7(14)4-8(10)9-5-12(19)16-13(21)17(9)6-11(15)18/h2-5H,6H2,1H3,(H2,15,18)(H,16,19,21)

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/30889221 | https://adisinsight.springer.com/drugs/800036418 | https://www.ncbi.nlm.nih.gov/pubmed/28685622

PF-06282999 is selective myeloperoxidase inactivator. PF-06282999 selectively activated human pregnane X receptor (PXR). Treatment of human HepaRG cells with PF-06282999 led to ∼14-fold induction in CYP3A4 mRNA and 5-fold increase in midazolam-1'-hydroxylase activity. [18F]-Fluoro-deoxy-glucose (FDG) was administered to Ldlr-/- mice with established atherosclerosis that had been treated with clinically relevant doses of PF-06282999, and reduced FDG signal was observed in animals treated with a dose of PF-06282999 that corresponded with reduced necrotic core area. PF-06282999 was developed for the treatment of acute coronary syndromes.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Myeloperoxidase 6 Target ID: CHEMBL2439 Sources: https://adisinsight.springer.com/drugs/800036418	Inhibitor 8504		1.9 µM [IC50]

C_max

Value	Dose	Analyte	Population
0.198 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28254951/	10 mg 3 times / day steady-state, oral dose: 10 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PF-06282999 plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
0.604 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28254951/	30 mg 3 times / day steady-state, oral dose: 30 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PF-06282999 plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
1.52 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28254951/	100 mg 3 times / day steady-state, oral dose: 100 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PF-06282999 plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
3.54 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28254951/	250 mg 3 times / day steady-state, oral dose: 250 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PF-06282999 plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
5.14 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28254951/	500 mg 2 times / day steady-state, oral dose: 500 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PF-06282999 plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
3799 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26608081/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	PF-06282999 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Analyte	Population
1.05 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28254951/	10 mg 3 times / day steady-state, oral dose: 10 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PF-06282999 plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
3.37 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28254951/	30 mg 3 times / day steady-state, oral dose: 30 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PF-06282999 plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
8.26 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28254951/	100 mg 3 times / day steady-state, oral dose: 100 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PF-06282999 plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
19.7 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28254951/	250 mg 3 times / day steady-state, oral dose: 250 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PF-06282999 plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
35.6 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28254951/	500 mg 2 times / day steady-state, oral dose: 500 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PF-06282999 plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
16950 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26608081/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	PF-06282999 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Analyte	Population
4.43 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28254951/	10 mg 3 times / day steady-state, oral dose: 10 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PF-06282999 plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
4.9 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28254951/	30 mg 3 times / day steady-state, oral dose: 30 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PF-06282999 plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
4.75 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28254951/	100 mg 3 times / day steady-state, oral dose: 100 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PF-06282999 plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
7.35 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28254951/	250 mg 3 times / day steady-state, oral dose: 250 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PF-06282999 plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
6.08 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28254951/	500 mg 2 times / day steady-state, oral dose: 500 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PF-06282999 plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
4.3 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26608081/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	PF-06282999 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
0.376% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28254951/			PF-06282999 plasma	Homo sapiens

PubMed

Title	Date	PubMed
Myeloperoxidase inhibition in mice alters atherosclerotic lesion composition.	2019	30889221
Induction of human cytochrome P450 3A4 by the irreversible myeloperoxidase inactivator PF-06282999 is mediated by the pregnane X receptor.	2018-07	28685622
Establishing Transcriptional Signatures to Differentiate PXR-, CAR-, and AhR-Mediated Regulation of Drug Metabolism and Transport Genes in Cryopreserved Human Hepatocytes.	2018-05	29440451
Examination of the Human Cytochrome P4503A4 Induction Potential of PF-06282999, an Irreversible Myeloperoxidase Inactivator: Integration of Preclinical, In Silico, and Biomarker Methodologies in the Prediction of the Clinical Outcome.	2017-05	28254951
Pharmacokinetics and Disposition of the Thiouracil Derivative PF-06282999, an Orally Bioavailable, Irreversible Inactivator of Myeloperoxidase Enzyme, Across Animals and Humans.	2016-02	26608081
Discovery of 2-(6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999): A Highly Selective Mechanism-Based Myeloperoxidase Inhibitor for the Treatment of Cardiovascular Diseases.	2015-11-12	26509551

Sample Use Guides

In Vivo Use Guide

5 and 15 mg/kg twice a day

Route of Administration: Oral

Name

Type

Language

1(2H)-PYRIMIDINEACETAMIDE, 6-(5-CHLORO-2-METHOXYPHENYL)-3,4-DIHYDRO-4-OXO-2-THIOXO-

Preferred Name

English

PF-06282999

Common Name

English

2-(6-(5-CHLORO-2-METHOXYPHENYL)-4-OXO-2-THIOXO-3,4-DIHYDROPYRIMIDIN-1(2H)-YL)ACETAMIDE

Systematic Name

English

Code System Code Type Description

PUBCHEM

71571306