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Also known as: 1095173-27-5, Pf-04449913, Pf 04449913, Daurismo, 1-((2r,4r)-2-(1h-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea, 1-[(2r,4r)-2-(1h-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(4-cyanophenyl)urea

Molecular Formula

C₂₁H₂₂N₆O

Molecular Weight

374.4 g/mol

InChI Key

SFNSLLSYNZWZQG-VQIMIIECSA-N

FDA UNII

K673DMO5H9

Glasdegib is an orally bioavailable small-molecule inhibitor of the Hedgehog (Hh) signaling pathway with potential antineoplastic activity. Glasdegib appears to inhibit Hh pathway signaling. The Hh signaling pathway plays an important role in cellular growth, differentiation and repair. Constitutive activation of Hh pathway signaling has been observed in various types of malignancies.

Glasdegib is a Hedgehog Pathway Inhibitor. The mechanism of action of glasdegib is as a Smoothened Receptor Antagonist.

1 2D Structure

Glasdegib

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(4-cyanophenyl)urea

2.1.2 InChI

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

2.1.3 InChI Key

SFNSLLSYNZWZQG-VQIMIIECSA-N

2.1.4 Canonical SMILES

CN1CCC(CC1C2=NC3=CC=CC=C3N2)NC(=O)NC4=CC=C(C=C4)C#N

2.1.5 Isomeric SMILES

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

2.2 Other Identifiers

2.2.1 UNII

K673DMO5H9

2.3 Synonyms

2.3.1 MeSH Synonyms

1. 1-(2-(1h-benzo(d)imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea

2. Daurismo

3. Pf-04449913

2.3.2 Depositor-Supplied Synonyms

1. 1095173-27-5

2. Pf-04449913

3. Pf 04449913

4. Daurismo

5. 1-((2r,4r)-2-(1h-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea

6. 1-[(2r,4r)-2-(1h-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(4-cyanophenyl)urea

7. K673dmo5h9

8. Chembl2043437

9. Pf-4449913

10. C21h22n6o

11. Glasdegib (pf-04449913)

12. Pf-913

13. Glasdegib [usan:inn]

14. Glasdegibum

15. Unii-k673dmo5h9

16. N-[(2r,4r)-2-(1h-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-n'-(4-cyanophenyl)urea

17. N-((2r,4r)-2-(1h-benzimidazol-2-yl)-1-methylpiperidin-4-yl)-n'-(4-cyanophenyl)urea

18. Glasdegib [inn]

19. Glasdegib [mi]

20. Glasdegib (usan/inn)

21. Glasdegib [usan]

22. Glasdegib [who-dd]

23. Pf-04449913;glasdegib

24. Gtpl8201

25. Schembl2068480

26. Glasdegib(pf-04449913)

27. Ex-a858

28. Chebi:145428

29. Dtxsid201025881

30. Amy38164

31. Vtb17327

32. Bdbm50385635

33. Mfcd25976839

34. Nsc775772

35. Zinc68251434

36. Ccg-268350

37. Db11978

38. Nsc-775772

39. Ncgc00378600-02

40. Ac-35176

41. Bs-14357

42. Hy-16391

43. S7160

44. D10636

45. J-690029

46. Q27077810

47. N-[(2r,4r)-2-(1h-benzimidazol-2-yl)-1-methyl-4-piperidinyl]-n'-(4-cyanophenyl)urea

48. 4-[(2r)-2-[(1r)-2,2,2-trifluoro-1-hydroxyethyl]-1-pyrrolidinyl]-2-(trifluoromethyl)-benzonitrile

2.4 Create Date

2009-03-03

3 Chemical and Physical Properties

Molecular Formula	C₂₁H₂₂N₆O
Molecular Weight	374.4 g/mol
XLogP3	2.4
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	4
Rotatable Bond Count	3
Exact Mass	374.18550935 g/mol
Monoisotopic Mass	374.18550935 g/mol
Topological Polar Surface Area	96.8 Å²
Heavy Atom Count	28
Formal Charge	0
Complexity	595
Isotope Atom Count	0
Defined Atom Stereocenter Count	2
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Drug Indication

Glasdegib, in combination with cytarabine, is indicated for the treatment of newly diagnosed acute myeloid leukemia in adult patients who are over 75 years old or that have co-morbidities that preclude intensive induction chemotherapy. Acute myeloid leukemia is characterized by abnormal production of myeloblasts, red cells, or platelets. It is considered a cancer of blood and bone marrow and it is the most common type of acute leukemia in adults.

FDA Label

Daurismo is indicated, in combination with low-dose cytarabine, for the treatment of newly diagnosed de novo or secondary acute myeloid leukaemia (AML) in adult patients who are not candidates for standard induction chemotherapy.

5 Pharmacology and Biochemistry

5.1 Pharmacology

In preclinical studies, glasdegib achieved a significant reduction in leukemic stem cell burden in xenograft models and a reduction in cell population expressing leukemic stem cell markers. In clinical trials, glasdegib demonstrated a marked downregulation of more than 80% of the expression of glioma-associated transcriptional regulator GL11 in skin. In this same study 8% of the studied individuals with acute myeloid leukemia achieved morphological complete remission while 31% achieved stable disease state. The latest clinical trial proved glasdegib to generate an overall survival of 8.3 months which was almost double to what has been observed in patients under low-dose cytarabine treatment. As well, there have been reports of dose-dependent QTc prolongation in patients administered with glasdegib.

5.2 FDA Pharmacological Classification

5.2.1 Active Moiety

GLASDEGIB

5.2.2 FDA UNII

K673DMO5H9

5.2.3 Pharmacological Classes

Smoothened Receptor Antagonists [MoA]; Hedgehog Pathway Inhibitor [EPC]

5.3 ATC Code

L01XX63

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01X - Other antineoplastic agents

L01XJ - Hedgehog pathway inhibitors

L01XJ03 - Glasdegib

5.4 Absorption, Distribution and Excretion

Absorption

Glasdegib presents a dose-proportional pharmacokinetic profile which is observed by the presence of a broad dose-proportional maximum plasma concentration. In this study and on a dose of 50 mg, the median time to reach a maximum concentration of 321 ng/ml was of 4 hours with an AUC of 9587 ng.h/ml. The oral bioavailability of glasdegib is reported to be of 55%. In a multiple dose study of 50 mg, the Cmax, tmax and AUC was reported to be 542 ng/ml, 4 h and 9310 ng.h/ml respectively. In this same study, the average concentration at a steady state was of 388 ng/ml. The absorption rates of glasdegib can be modified by the concomitant consumption of a high-fat, high-calorie meal.

Route of Elimination

From the administered dose of glasdegib, 49% is eliminated in the urine from which 17% is excreted as the unchanged form while 42% is eliminated in feces where 20% represents the unchanged form.

Volume of Distribution

Glasdegib reported volume of distribution in a dose of 50 mg is of 225 L.

Clearance

The clearance rate of 50 mg of glasdegib is reported to be of 5.22 L/h.

5.5 Metabolism/Metabolites

After oral administration, glasdegib was primarily metabolized by CYP3A4 with minor contributions of CYP2C8 and UGT1A9. The amount of unchanged glasdegib in plasma accounts only for 69% of the administered dose.

5.6 Biological Half-Life

The reported half-life of glasdegib is of 17.4 hours.

5.7 Mechanism of Action

Glasdegib is a potent and selective inhibitor of the hedgehog signaling pathway that acts by binding to the smoothened (SMO) receptor. The hedgehog signaling pathway is involved in maintenance of neural and skin stem cells. In this pathway, the binding of specific ligands to the transmembrane receptor patched (PTCH1) allows the activation of the transcriptional regulators GL11, GL12 and modulation of the gene expression through SMO-mediated signaling. The aberrant activation of the hedgehog pathway is thought to be implicated in the pathogenesis of chronic myeloid leukemia, medulloblastoma and basal cell carcinoma due to the hyperproliferative state that a modification on this pathway will produce.

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