GLASDEGIB MALEATE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C21H22N6O.C4H4O4
Molecular Weight	490.5111
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OC(=O)\C=C/C(O)=O.CN1CC[C@H](C[C@@H]1C2=NC3=CC=CC=C3N2)NC(=O)NC4=CC=C(C=C4)C#N

InChI

InChIKey=VJCVKWFBWAVYOC-UIXXXISESA-N

InChI=1S/C21H22N6O.C4H4O4/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;5-3(6)1-2-4(7)8/h2-9,16,19H,10-12H2,1H3,(H,25,26)(H2,23,24,28);1-2H,(H,5,6)(H,7,8)/b;2-1-/t16-,19-;/m1./s1

HIDE SMILES / InChI

Molecular Formula	C4H4O4
Molecular Weight	116.0722
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	1
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 2778

Conditions

Condition	Modality	Highest Phase	Product
Acute myeloid leukemia 136 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210656s000lbl.pdf	Primary	Approved 8429	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 58 Sources: http://adisinsight.springer.com/drugs/800030686	Primary	Phase II 1132	Unknown Approved Use Unknown
Solid tumors 145 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25388167	Primary	Phase I 428	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) n = 8 Health Status: unhealthy Condition: Advanced Solid Tumors Age Group: 61.0 years (range: 27–76 years) Sex: M+F Population Size: 8 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) n = 7 Health Status: unhealthy Condition: Advanced Solid Tumors Age Group: 61.0 years (range: 27–76 years) Sex: M+F Population Size: 7 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) n = 9 Health Status: unhealthy Condition: myeloid malignancies Age Group: 69 years (range: 25–89 years) Sex: M+F Population Size: 9 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) n = 5 Health Status: unhealthy Condition: myeloid malignancies Age Group: 69 years (range: 25–89 years) Sex: M+F Population Size: 5 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) n = 8 Health Status: unhealthy Condition: myeloid malignancies Age Group: 69 years (range: 25–89 years) Sex: M+F Population Size: 8 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 1767	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2B6 810 CYP2C8 911 CYP2C19 1478 CYP3A 214 P-gp 1461 BCRP 699 MATE1 306 MATE2 263 OATP1B1 788 OATP1B3 706 OAT1 599 OAT3 642 OCT2 647 UGT1A4 77 UGT1A6 108 UGT2B7 146 UGT2B15 64 CYP1A 72 CYP2E1 882 UGT1A9 116	CYP3A 191 CYP2C8 693 UGT1A9 380 P-gp 1537 BCRP 561 OAT1 326 OAT3 339 OCT2 355 MATE1 135 MATE2 96 OATP1B1 406 OATP1B3 350	CYP1A2 701 CYP2B6 547 CYP3A 129

Drug as perpetrator

Target	Modality	Activity
OATP1B1 803	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no [IC50 26 uM]
OATP1B3 715	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no [IC50 26 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no [IC50 88 uM]
UGT1A4 80	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=18 Page: 18.0	no [IC50 >131 uM]
UGT1A6 141	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=18 Page: 18.0	no [IC50 >131 uM]
UGT2B15 64	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=18 Page: 18.0	no [IC50 >131 uM]
UGT2B7 157	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=18 Page: 18.0	no [IC50 >131 uM]
OAT1 603	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no [IC50 >50 uM]
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no [IC50 >50 uM]
OCT2 648	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no [IC50 >50 uM]
CYP1A 121	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=39 Page: 39.0	no [IC50 >94 uM]
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no [IC50 >94 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no [IC50 >94 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no [IC50 >94 uM]
CYP3A 298	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no [IC50 >94 uM]
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=39 Page: 39.0	no
CYP3A 298	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	no
MATE2 263	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	yes [IC50 1.2 uM]
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	yes [IC50 4.6 uM]
MATE1 308	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	yes [IC50 4.9 uM]
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	yes
UGT1A9 121	inhibitor 3277 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 135	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
MATE2 96	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
OAT1 326	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
OAT3 339	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
OATP1B1 406	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
OATP1B3 350	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
OCT2 355	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=41 Page: 41.0	no
BCRP 561	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	yes
CYP2C8 693	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=11 Page: 11.0	yes
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=12 Page: 12.0	yes
UGT1A9 380	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf#page=11 Page: 11.0	yes
CYP3A 191	substrate 3367 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 `Sat Dec 16 14:14:14 GMT 2023` Edited by `admin` on `Sat Dec 16 14:14:14 GMT 2023`
Record UNII	TH2EV99S4Z
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

GLASDEGIB MALEATE

Common Name

English

DAURISMO

Brand Name

English

GLASDEGIB MALEATE [ORANGE BOOK]

Common Name

English

PF-04449913 MALEATE

Code

English

GLASDEGIB MALEATE [JAN]

Common Name

English

Glasdegib maleate [WHO-DD]

Common Name

English

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

Systematic Name

English

Classification Tree Code System Code

EU-Orphan Drug

EU/3/17/1923