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Details

Stereochemistry ABSOLUTE
Molecular Formula C21H22N6O
Molecular Weight 374.439
Optical Activity UNSPECIFIED
Defined Stereocenters 2 / 2
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of GLASDEGIB

SMILES

CN1CC[C@H](C[C@@H]1C2=NC3=C(N2)C=CC=C3)NC(=O)NC4=CC=C(C=C4)C#N

InChI

InChIKey=SFNSLLSYNZWZQG-VQIMIIECSA-N
InChI=1S/C21H22N6O/c1-27-11-10-16(24-21(28)23-15-8-6-14(13-22)7-9-15)12-19(27)20-25-17-4-2-3-5-18(17)26-20/h2-9,16,19H,10-12H2,1H3,(H,25,26)(H2,23,24,28)/t16-,19-/m1/s1

HIDE SMILES / InChI

Molecular Formula C21H22N6O
Molecular Weight 374.439
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry
Defined Stereocenters 2 / 2
E/Z Centers 0
Optical Activity UNSPECIFIED

Description

PF-04449913 is a potent and selective inhibitor of the Hh signaling pathway through binding to the target, smoothened. PF-04449913 inhibits Hh signaling in vitro and has demonstrated significant antitumor activity in vivo. In the clinic, PF-04449913 is being evaluated both in hematological and solid malignancies, with a phase II trial currently underway in both fit and unfit patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). Treatment-related adverse-events were nausea, dizziness, somnolence, QT prolongation and pruritus. Based on pre-clinical assessments, CYP3A4 is believed to be primarily involved in the metabolism of PF-04449913 that is why PF-04449913 plasma exposures and peak concentrations were increased following concurrent administration of ketoconazole (CYP3A4 inhibitor).

Originator

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
Conditions
PubMed

PubMed

TitleDatePubMed
Discovery of PF-04449913, a Potent and Orally Bioavailable Inhibitor of Smoothened.
2012 Feb 9
Patents

Sample Use Guides

In Vivo Use Guide
100 mg daily in 4-week cycles for a total of 4 cycles. Dose escalation to 200 mg will be provided for patients who do not have at least hematologic improvement following 2 cycles, and dose reduction to 50 mg will be permitted for patients with significant toxicity.
Route of Administration: Oral
In Vitro Use Guide
Incubation of primary AML cells with PF‐913 (1 or 5 uM) attenuated Smoothened‐targeting gene transcripts that were activated by the addition of sonic hedgehog, and reduced the fraction of CD34+CD38− cells.
Substance Class Chemical
Created
by admin
on Mon Oct 21 23:04:24 UTC 2019
Edited
by admin
on Mon Oct 21 23:04:24 UTC 2019
Record UNII
K673DMO5H9
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
GLASDEGIB
INN   USAN   WHO-DD  
INN   USAN  
Official Name English
UREA, N-((2R,4R)-2-(1H-BENZIMIDAZOL-2-YL)-1-METHYL-4-PIPERIDINYL)-N'-(4-CYANOPHENYL)-
Systematic Name English
GLASDEGIB [INN]
Common Name English
GLASDEGIB [USAN]
Common Name English
N-((2R,4R)-2-(1H-BENZIMIDAZOL-2-YL)-1-METHYLPIPERIDIN-4-YL)-N'-(4-CYANOPHENYL)UREA
Systematic Name English
GLASDEGIB [WHO-DD]
Common Name English
PF-04449913
Code English
PF-4449913
Code English
Classification Tree Code System Code
NCI_THESAURUS C2189
Created by admin on Mon Oct 21 23:04:24 UTC 2019 , Edited by admin on Mon Oct 21 23:04:24 UTC 2019
FDA ORPHAN DRUG 585517
Created by admin on Mon Oct 21 23:04:24 UTC 2019 , Edited by admin on Mon Oct 21 23:04:24 UTC 2019
FDA ORPHAN DRUG 608617
Created by admin on Mon Oct 21 23:04:24 UTC 2019 , Edited by admin on Mon Oct 21 23:04:24 UTC 2019
NDF-RT N0000184149
Created by admin on Mon Oct 21 23:04:24 UTC 2019 , Edited by admin on Mon Oct 21 23:04:24 UTC 2019
Code System Code Type Description
ChEMBL
CHEMBL2043437
Created by admin on Mon Oct 21 23:04:24 UTC 2019 , Edited by admin on Mon Oct 21 23:04:24 UTC 2019
PRIMARY
NCI_THESAURUS
C84862
Created by admin on Mon Oct 21 23:04:24 UTC 2019 , Edited by admin on Mon Oct 21 23:04:24 UTC 2019
PRIMARY
EVMPD
SUB179278
Created by admin on Mon Oct 21 23:04:24 UTC 2019 , Edited by admin on Mon Oct 21 23:04:24 UTC 2019
PRIMARY
INN
9930
Created by admin on Mon Oct 21 23:04:24 UTC 2019 , Edited by admin on Mon Oct 21 23:04:24 UTC 2019
PRIMARY
PUBCHEM
25166913
Created by admin on Mon Oct 21 23:04:24 UTC 2019 , Edited by admin on Mon Oct 21 23:04:24 UTC 2019
PRIMARY
WIKIPEDIA
Glasdegib
Created by admin on Mon Oct 21 23:04:24 UTC 2019 , Edited by admin on Mon Oct 21 23:04:24 UTC 2019
PRIMARY
CAS
1095173-27-5
Created by admin on Mon Oct 21 23:04:24 UTC 2019 , Edited by admin on Mon Oct 21 23:04:24 UTC 2019
PRIMARY
Related Record Type Details
TRANSPORTER -> INHIBITOR
SALT/SOLVATE -> PARENT
EXCRETED UNCHANGED
Following a single oral dose of 100 mg radiolabeled glasdegib, 49% of the administered dose was eliminated in the urine (17% unchanged), and 42% was eliminated in the feces (20% unchanged).
FECAL; URINE
TRANSPORTER -> INHIBITOR
TRANSPORTER -> INHIBITOR
BINDER->LIGAND
Glasdegib is 91% bound to human plasma proteins in vitro
METABOLIC ENZYME -> SUBSTRATE
Glasdegib is metabolized primarily by the CYP3A4 pathway.
MAJOR
TRANSPORTER -> SUBSTRATE
SALT/SOLVATE -> PARENT
TRANSPORTER -> INHIBITOR
METABOLIC ENZYME -> SUBSTRATE
Glasdegib is metabolized primarily by the CYP3A4 pathway, with minor contributions by CYP2C8 and UGT1A9
MINOR
TARGET -> INHIBITOR
COMPETITIVE INHIBITOR
IC50
TRANSPORTER -> SUBSTRATE
METABOLIC ENZYME -> SUBSTRATE
Glasdegib is metabolized primarily by the CYP3A4 pathway, with minor contributions by CYP2C8 and UGT1A9
MINOR
Related Record Type Details
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
Biological Half-life PHARMACOKINETIC ONCE DAILY DOSING

Tmax PHARMACOKINETIC ONCE DAILY DOSING

Volume of Distribution PHARMACOKINETIC