GLASDEGIB HYDROCHLORIDE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C21H22N6O.ClH
Molecular Weight	410.9
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

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

InChI

InChIKey=OCHAAZGYSAHXOF-LJLRIERRSA-N

InChI=1S/C21H22N6O.ClH/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);1H/t16-,19-;/m1./s1

HIDE SMILES / InChI

Molecular Formula	ClH
Molecular Weight	36.461
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Molecular Formula	C21H22N6O
Molecular Weight	374.439
Charge	0
Count

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

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/24944041
Curator's Comment: description was created based on several sources, including: 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

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Smoothened homolog 20 Target ID: CHEMBL5971 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24900436	Antagonist 2849

Conditions

Condition	Modality	Highest Phase	Product
Acute myeloid leukemia 141 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210656s000lbl.pdf	Primary	Approved 8583	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 2018
Myelodysplastic syndromes 61 Sources: http://adisinsight.springer.com/drugs/800030686	Primary	Phase II 1147	Unknown Approved Use Unknown
Solid tumors 147 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25388167	Primary	Phase I 438	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
1252 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210656s000lbl.pdf	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

Value	Dose	Co-administered	Analyte	Population
17210 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210656s000lbl.pdf	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

T_1/2

Value	Dose	Co-administered	Analyte	Population
17.4 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210656s000lbl.pdf	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

F_unbound

Value	Dose	Co-administered	Analyte	Population
9% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210656s000lbl.pdf	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

Dose	Population	Adverse 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: https://pubmed.ncbi.nlm.nih.gov/25388167	unhealthy, 61.0 years (range: 27–76 years) Health Status: unhealthy Age Group: 61.0 years (range: 27–76 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/25388167	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: https://pubmed.ncbi.nlm.nih.gov/25388167
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: https://pubmed.ncbi.nlm.nih.gov/25388167	unhealthy, 61.0 years (range: 27–76 years) Health Status: unhealthy Age Group: 61.0 years (range: 27–76 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/25388167	Disc. AE: Dehydration, Fatigue... AEs leading to discontinuation/dose reduction: Dehydration (2 patients) Fatigue (2 patients) Nausea (2 patients) Vomiting (2 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/25388167
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: https://pubmed.ncbi.nlm.nih.gov/26688487	unhealthy, 69 years (range: 25–89 years) Health Status: unhealthy Age Group: 69 years (range: 25–89 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/26688487	Sources: https://pubmed.ncbi.nlm.nih.gov/26688487
600 mg 1 times / day steady, oral Dose: 600 mg, 1 times / day Route: oral Route: steady Dose: 600 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/26688487	unhealthy, 69 years (range: 25–89 years) Health Status: unhealthy Age Group: 69 years (range: 25–89 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/26688487	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: https://pubmed.ncbi.nlm.nih.gov/26688487
80 mg 1 times / day steady, oral Dose: 80 mg, 1 times / day Route: oral Route: steady Dose: 80 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/26688487	unhealthy, 69 years (range: 25–89 years) Health Status: unhealthy Age Group: 69 years (range: 25–89 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/26688487	DLT: Hypoxia, Pleural effusion... Dose limiting toxicities: Hypoxia (grade 3, 17%) Pleural effusion (grade 3, 17%) Sources: https://pubmed.ncbi.nlm.nih.gov/26688487
100 mg 1 times / day multiple, oral Dose: 100 mg, 1 times / day Route: oral Route: multiple Dose: 100 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210656s000lbl.pdf	pregnant Health Status: pregnant Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210656s000lbl.pdf	Other AEs: Fetal damage... Other AEs: Fetal damage (grade 5) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210656s000lbl.pdf

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
	inhibitor 2438	inhibitor 2507

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 2153 CYP2B6 926 CYP2C8 1057 CYP2C19 2057 CYP3A 227 P-gp 1741 BCRP 910 MATE1 415 MATE2 267 OATP1B1 1079 OATP1B3 961 OAT1 725 OAT3 747 OCT2 779 UGT1A4 98 UGT1A6 136 UGT2B7 197 UGT2B15 84 CYP1A 70 CYP2E1 1060 UGT1A9 148	CYP3A 220 CYP2C8 810 UGT1A9 423 P-gp 2052 BCRP 697 OAT1 395 OAT3 391 OCT2 434 MATE1 182 MATE2 98 OATP1B1 503 OATP1B3 435	CYP1A2 832 CYP2B6 669 CYP3A 142

Drug as perpetrator

Target	Modality	Activity
OATP1B1 1095	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no [IC50 26 uM]
OATP1B3 970	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no [IC50 26 uM]
CYP2D6 2546	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no [IC50 88 uM]
UGT1A4 100	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=18 Page: 18.0	no [IC50 >131 uM]
UGT1A6 171	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=18 Page: 18.0	no [IC50 >131 uM]
UGT2B15 84	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=18 Page: 18.0	no [IC50 >131 uM]
UGT2B7 210	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=18 Page: 18.0	no [IC50 >131 uM]
OAT1 730	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no [IC50 >50 uM]
OAT3 749	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no [IC50 >50 uM]
OCT2 782	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no [IC50 >50 uM]
CYP1A 122	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=39 Page: 39.0	no [IC50 >94 uM]
CYP2B6 1160	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no [IC50 >94 uM]
CYP2C19 2141	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no [IC50 >94 uM]
CYP2C9 2497	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no [IC50 >94 uM]
CYP3A 317	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no [IC50 >94 uM]
CYP1A2 2333	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no
CYP1A2 2333	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no
CYP2B6 1160	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no
CYP2C8 1117	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no
CYP2E1 1146	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=39 Page: 39.0	no
CYP3A 317	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no
MATE2 267	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	yes [IC50 1.2 uM]
BCRP 985	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	yes [IC50 4.6 uM]
MATE1 416	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	yes [IC50 4.9 uM]
P-gp 1932	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	yes
UGT1A9 155	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=39 Page: 39.0	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
MATE1 182	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
MATE2 98	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
OAT1 395	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
OAT3 391	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
OATP1B1 503	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
OATP1B3 435	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
OCT2 434	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
BCRP 697	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	yes
CYP2C8 810	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=11 Page: 11.0	yes
P-gp 2052	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	yes
UGT1A9 423	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=11 Page: 11.0	yes
CYP3A 220	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=11 Page: 11.0	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 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=11 Page: 11.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:145428	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:145428
ChemicalBook	CB82658197	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB82658197
MolPort	MolPort-035-789-706	https://www.molport.com/shop/molecule-link/MolPort-035-789-706
ZINC	ZINC000068251434	http://zinc15.docking.org/substances/ZINC000068251434

PubMed

Title	Date	PubMed
Discovery of PF-04449913, a Potent and Orally Bioavailable Inhibitor of Smoothened.	2012 Feb 9	24900436

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 Mar 31 22:56:08 GMT 2025` Edited by `admin` on `Mon Mar 31 22:56:08 GMT 2025`
Record UNII	4Y7R3PBO4V
Record Status	`Validated (UNII)`
Record Version

Download

Name

Type

Language

GLASDEGIB HYDROCHLORIDE

Common Name

English

UREA, N-((2R,4R)-2-(1H-BENZIMIDAZOL-2-YL)-1-METHYL-4-PIPERIDINYL)-N'-(4-CYANOPHENYL)-, HYDROCHLORIDE (1:1)

Preferred Name

English

Glasdegib hydrochloride [WHO-DD]

Common Name

English

Code System Code Type Description

SMS_ID

100000177200