U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C21H22N6O
Molecular Weight 374.4398
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@]1([H])c2[nH]c3ccccc3n2)N=C(Nc4ccc(cc4)C#N)O

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 374.4398
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 2 / 2
E/Z Centers 0
Optical Activity UNSPECIFIED

Description
Curator's Comment:: http://adisinsight.springer.com/drugs/800030686 | http://www.pharmacodia.com/yaodu/html/v1/chemicals/86f3f50a6f945bbfa351e55faac043fb.html

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

Curator's Comment:: # Pfizer

Approval Year

TargetsConditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
DAURISMO

Approved Use

Daurismo is specifically indicated for use in combination with low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukemia in adult patients who are ≥75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.

Launch Date

1542672000000
Primary
Primary
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
1252 ng/mL
100 mg 1 times / day multiple, oral
dose: 100 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
GLASDEGIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
17210 ng × h/mL
100 mg 1 times / day multiple, oral
dose: 100 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
GLASDEGIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
17.4 h
100 mg 1 times / day multiple, oral
dose: 100 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
GLASDEGIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
9%
100 mg 1 times / day multiple, oral
dose: 100 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
GLASDEGIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
640 mg 1 times / day steady, oral
Highest studied dose
Dose: 640 mg, 1 times / day
Route: oral
Route: steady
Dose: 640 mg, 1 times / day
Sources:
unhealthy, 61.0 years (range: 27–76 years)
Health Status: unhealthy
Age Group: 61.0 years (range: 27–76 years)
Sex: M+F
Sources:
DLT: Fatigue, Dehydration...
Dose limiting toxicities:
Fatigue (grade 2, 1 patient)
Dehydration (grade 2-3, 2 patients)
Dizziness (grade 2, 1 patient)
Hypotension (grade 2, 1 patient)
Nausea (grade 3, 1 patient)
Vomiting (grade 3, 1 patient)
Sources:
320 mg 1 times / day steady, oral
MTD
Dose: 320 mg, 1 times / day
Route: oral
Route: steady
Dose: 320 mg, 1 times / day
Sources:
unhealthy, 61.0 years (range: 27–76 years)
Health Status: unhealthy
Age Group: 61.0 years (range: 27–76 years)
Sex: M+F
Sources:
Disc. AE: Dehydration, Fatigue...
AEs leading to
discontinuation/dose reduction:
Dehydration (2 patients)
Fatigue (2 patients)
Nausea (2 patients)
Vomiting (2 patients)
Sources:
400 mg 1 times / day steady, oral
MTD
Dose: 400 mg, 1 times / day
Route: oral
Route: steady
Dose: 400 mg, 1 times / day
Sources:
unhealthy, 69 years (range: 25–89 years)
Health Status: unhealthy
Age Group: 69 years (range: 25–89 years)
Sex: M+F
Sources:
600 mg 1 times / day steady, oral
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 69 years (range: 25–89 years)
Health Status: unhealthy
Age Group: 69 years (range: 25–89 years)
Sex: M+F
Sources:
DLT: Peripheral oedema...
Disc. AE: Electrocardiogram QTc interval prolonged...
Dose limiting toxicities:
Peripheral oedema (grade 3, 20%)
AEs leading to
discontinuation/dose reduction:
Electrocardiogram QTc interval prolonged (grade 3, 4 patients)
Sources:
80 mg 1 times / day steady, oral
Dose: 80 mg, 1 times / day
Route: oral
Route: steady
Dose: 80 mg, 1 times / day
Sources:
unhealthy, 69 years (range: 25–89 years)
Health Status: unhealthy
Age Group: 69 years (range: 25–89 years)
Sex: M+F
Sources:
DLT: Hypoxia, Pleural effusion...
Dose limiting toxicities:
Hypoxia (grade 3, 17%)
Pleural effusion (grade 3, 17%)
Sources:
100 mg 1 times / day multiple, oral
Dose: 100 mg, 1 times / day
Route: oral
Route: multiple
Dose: 100 mg, 1 times / day
Sources:
pregnant
Other AEs: Fetal damage...
AEs

AEs

AESignificanceDosePopulation
Dizziness grade 2, 1 patient
DLT
640 mg 1 times / day steady, oral
Highest studied dose
Dose: 640 mg, 1 times / day
Route: oral
Route: steady
Dose: 640 mg, 1 times / day
Sources:
unhealthy, 61.0 years (range: 27–76 years)
Health Status: unhealthy
Age Group: 61.0 years (range: 27–76 years)
Sex: M+F
Sources:
Hypotension grade 2, 1 patient
DLT
640 mg 1 times / day steady, oral
Highest studied dose
Dose: 640 mg, 1 times / day
Route: oral
Route: steady
Dose: 640 mg, 1 times / day
Sources:
unhealthy, 61.0 years (range: 27–76 years)
Health Status: unhealthy
Age Group: 61.0 years (range: 27–76 years)
Sex: M+F
Sources:
Fatigue grade 2, 1 patient
DLT, Disc. AE
640 mg 1 times / day steady, oral
Highest studied dose
Dose: 640 mg, 1 times / day
Route: oral
Route: steady
Dose: 640 mg, 1 times / day
Sources:
unhealthy, 61.0 years (range: 27–76 years)
Health Status: unhealthy
Age Group: 61.0 years (range: 27–76 years)
Sex: M+F
Sources:
Dehydration grade 2-3, 2 patients
DLT, Disc. AE
640 mg 1 times / day steady, oral
Highest studied dose
Dose: 640 mg, 1 times / day
Route: oral
Route: steady
Dose: 640 mg, 1 times / day
Sources:
unhealthy, 61.0 years (range: 27–76 years)
Health Status: unhealthy
Age Group: 61.0 years (range: 27–76 years)
Sex: M+F
Sources:
Nausea grade 3, 1 patient
DLT, Disc. AE
640 mg 1 times / day steady, oral
Highest studied dose
Dose: 640 mg, 1 times / day
Route: oral
Route: steady
Dose: 640 mg, 1 times / day
Sources:
unhealthy, 61.0 years (range: 27–76 years)
Health Status: unhealthy
Age Group: 61.0 years (range: 27–76 years)
Sex: M+F
Sources:
Vomiting grade 3, 1 patient
DLT, Disc. AE
640 mg 1 times / day steady, oral
Highest studied dose
Dose: 640 mg, 1 times / day
Route: oral
Route: steady
Dose: 640 mg, 1 times / day
Sources:
unhealthy, 61.0 years (range: 27–76 years)
Health Status: unhealthy
Age Group: 61.0 years (range: 27–76 years)
Sex: M+F
Sources:
Dehydration 2 patients
Disc. AE
320 mg 1 times / day steady, oral
MTD
Dose: 320 mg, 1 times / day
Route: oral
Route: steady
Dose: 320 mg, 1 times / day
Sources:
unhealthy, 61.0 years (range: 27–76 years)
Health Status: unhealthy
Age Group: 61.0 years (range: 27–76 years)
Sex: M+F
Sources:
Fatigue 2 patients
Disc. AE
320 mg 1 times / day steady, oral
MTD
Dose: 320 mg, 1 times / day
Route: oral
Route: steady
Dose: 320 mg, 1 times / day
Sources:
unhealthy, 61.0 years (range: 27–76 years)
Health Status: unhealthy
Age Group: 61.0 years (range: 27–76 years)
Sex: M+F
Sources:
Nausea 2 patients
Disc. AE
320 mg 1 times / day steady, oral
MTD
Dose: 320 mg, 1 times / day
Route: oral
Route: steady
Dose: 320 mg, 1 times / day
Sources:
unhealthy, 61.0 years (range: 27–76 years)
Health Status: unhealthy
Age Group: 61.0 years (range: 27–76 years)
Sex: M+F
Sources:
Vomiting 2 patients
Disc. AE
320 mg 1 times / day steady, oral
MTD
Dose: 320 mg, 1 times / day
Route: oral
Route: steady
Dose: 320 mg, 1 times / day
Sources:
unhealthy, 61.0 years (range: 27–76 years)
Health Status: unhealthy
Age Group: 61.0 years (range: 27–76 years)
Sex: M+F
Sources:
Peripheral oedema grade 3, 20%
DLT
600 mg 1 times / day steady, oral
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 69 years (range: 25–89 years)
Health Status: unhealthy
Age Group: 69 years (range: 25–89 years)
Sex: M+F
Sources:
Electrocardiogram QTc interval prolonged grade 3, 4 patients
Disc. AE
600 mg 1 times / day steady, oral
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 69 years (range: 25–89 years)
Health Status: unhealthy
Age Group: 69 years (range: 25–89 years)
Sex: M+F
Sources:
Hypoxia grade 3, 17%
DLT
80 mg 1 times / day steady, oral
Dose: 80 mg, 1 times / day
Route: oral
Route: steady
Dose: 80 mg, 1 times / day
Sources:
unhealthy, 69 years (range: 25–89 years)
Health Status: unhealthy
Age Group: 69 years (range: 25–89 years)
Sex: M+F
Sources:
Pleural effusion grade 3, 17%
DLT
80 mg 1 times / day steady, oral
Dose: 80 mg, 1 times / day
Route: oral
Route: steady
Dose: 80 mg, 1 times / day
Sources:
unhealthy, 69 years (range: 25–89 years)
Health Status: unhealthy
Age Group: 69 years (range: 25–89 years)
Sex: M+F
Sources:
Fetal damage grade 5
100 mg 1 times / day multiple, oral
Dose: 100 mg, 1 times / day
Route: oral
Route: multiple
Dose: 100 mg, 1 times / day
Sources:
pregnant
Overview

Overview

CYP3A4CYP2C9CYP2D6hERG


Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
no [IC50 26 uM]
no [IC50 26 uM]
no [IC50 88 uM]
no [IC50 >131 uM]
no [IC50 >131 uM]
no [IC50 >131 uM]
no [IC50 >131 uM]
no [IC50 >50 uM]
no [IC50 >50 uM]
no [IC50 >50 uM]
no [IC50 >94 uM]
no [IC50 >94 uM]
no [IC50 >94 uM]
no [IC50 >94 uM]
no [IC50 >94 uM]
no
no
no
no
no
no
yes [IC50 1.2 uM]
yes [IC50 4.6 uM]
yes [IC50 4.9 uM]
yes
yes
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
no
no
no
no
no
no
no
yes
yes
yes
yes
yes
yes (co-administration study)
Comment: Co-administration of ketoconazole (a strong inhibitor of CYP3A4: 400 mg daily for 7 days) with single dose of DAURISMO (200 mg) increased the glasdegib AUCinf by 2.4-fold (90% CI: 2.1, 2.7) and Cmax by 1.4-fold
Page: 11
PubMed

PubMed

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

Sample Use Guides

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
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 Sat Jun 26 03:30:49 UTC 2021
Edited
by admin
on Sat Jun 26 03:30:49 UTC 2021
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 [MI]
Common 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 Sat Jun 26 03:30:49 UTC 2021 , Edited by admin on Sat Jun 26 03:30:49 UTC 2021
FDA ORPHAN DRUG 585517
Created by admin on Sat Jun 26 03:30:49 UTC 2021 , Edited by admin on Sat Jun 26 03:30:49 UTC 2021
FDA ORPHAN DRUG 608617
Created by admin on Sat Jun 26 03:30:49 UTC 2021 , Edited by admin on Sat Jun 26 03:30:49 UTC 2021
NDF-RT N0000184149
Created by admin on Sat Jun 26 03:30:49 UTC 2021 , Edited by admin on Sat Jun 26 03:30:49 UTC 2021
Code System Code Type Description
LACTMED
Glasdegib
Created by admin on Sat Jun 26 03:30:49 UTC 2021 , Edited by admin on Sat Jun 26 03:30:49 UTC 2021
PRIMARY
ChEMBL
CHEMBL2043437
Created by admin on Sat Jun 26 03:30:49 UTC 2021 , Edited by admin on Sat Jun 26 03:30:49 UTC 2021
PRIMARY
NCI_THESAURUS
C84862
Created by admin on Sat Jun 26 03:30:49 UTC 2021 , Edited by admin on Sat Jun 26 03:30:49 UTC 2021
PRIMARY
DRUG CENTRAL
5304
Created by admin on Sat Jun 26 03:30:49 UTC 2021 , Edited by admin on Sat Jun 26 03:30:49 UTC 2021
PRIMARY
MERCK INDEX
M12133
Created by admin on Sat Jun 26 03:30:49 UTC 2021 , Edited by admin on Sat Jun 26 03:30:49 UTC 2021
PRIMARY
EVMPD
SUB179278
Created by admin on Sat Jun 26 03:30:49 UTC 2021 , Edited by admin on Sat Jun 26 03:30:49 UTC 2021
PRIMARY
DRUG BANK
DB11978
Created by admin on Sat Jun 26 03:30:49 UTC 2021 , Edited by admin on Sat Jun 26 03:30:49 UTC 2021
PRIMARY
FDA UNII
K673DMO5H9
Created by admin on Sat Jun 26 03:30:49 UTC 2021 , Edited by admin on Sat Jun 26 03:30:49 UTC 2021
PRIMARY
INN
9930
Created by admin on Sat Jun 26 03:30:49 UTC 2021 , Edited by admin on Sat Jun 26 03:30:49 UTC 2021
PRIMARY
PUBCHEM
25166913
Created by admin on Sat Jun 26 03:30:49 UTC 2021 , Edited by admin on Sat Jun 26 03:30:49 UTC 2021
PRIMARY
WIKIPEDIA
Glasdegib
Created by admin on Sat Jun 26 03:30:49 UTC 2021 , Edited by admin on Sat Jun 26 03:30:49 UTC 2021
PRIMARY
RXCUI
2105845
Created by admin on Sat Jun 26 03:30:49 UTC 2021 , Edited by admin on Sat Jun 26 03:30:49 UTC 2021
PRIMARY
CAS
1095173-27-5
Created by admin on Sat Jun 26 03:30:49 UTC 2021 , Edited by admin on Sat Jun 26 03:30:49 UTC 2021
PRIMARY
Related Record Type Details
SALT/SOLVATE -> PARENT
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
TARGET -> INHIBITOR
COMPETITIVE INHIBITOR
IC50
TRANSPORTER -> INHIBITOR
METABOLIC ENZYME -> SUBSTRATE
Glasdegib is metabolized primarily by the CYP3A4 pathway, with minor contributions by CYP2C8 and UGT1A9
MINOR
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
METABOLITE -> PARENT
Glasdegib was the most abundant circulating component in plasma, constituting 69% of plasma radioactivity, with minor circulating metabolites each being <8% of radioactivity.
METABOLITE -> PARENT
Glasdegib was the most abundant circulating component in plasma, constituting 69% of plasma radioactivity, with minor circulating metabolites each being <8% of radioactivity.
METABOLITE -> PARENT
Glasdegib was the most abundant circulating component in plasma, constituting 69% of plasma radioactivity, with minor circulating metabolites each being <8% of radioactivity.
METABOLITE -> PARENT
Glasdegib was the most abundant circulating component in plasma, constituting 69% of plasma radioactivity, with minor circulating metabolites each being <8% of radioactivity.
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