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Belumosudil

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5 US Patents
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Synopsis

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Chemistry

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Also known as: 911417-87-3, Slx-2119, Belumosudil, Kd-025, Kd025, Rock inhibitor 2

Molecular Formula

C₂₆H₂₄N₆O₂

Molecular Weight

452.5 g/mol

InChI Key

GKHIVNAUVKXIIY-UHFFFAOYSA-N

FDA UNII

834YJF89WO

Belumosudil is an orally bioavailable inhibitor of Rho-associated coiled-coil kinase 2 (ROCK2; ROCK-II), with potential immunomodulating activity. Upon oral administration, belumosudil binds to and inhibits the serine/threonine kinase activity of ROCK2. This inhibits ROCK2-mediated signal transduction pathways and modulates various pro- and anti-inflammatory immune cell responses through the regulation of signal transducer and activator of transcription 3 and 5 (STAT3/STAT5) phosphorylation. This downregulates pro-inflammatory Th17 cells and increases regulatory T (Treg) cells. Belumosudil also inhibits ROCK2-mediated fibrotic processes, including stress fiber formation, myofibroblast activation and pro-fibrotic gene transcription. ROCK2 is upregulated in various diseases, including various fibrotic, neurodegenerative and autoimmune diseases.

1 2D Structure

Belumosudil

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

2-[3-[4-(1H-indazol-5-ylamino)quinazolin-2-yl]phenoxy]-N-propan-2-ylacetamide

2.1.2 InChI

InChI=1S/C26H24N6O2/c1-16(2)28-24(33)15-34-20-7-5-6-17(13-20)25-30-23-9-4-3-8-21(23)26(31-25)29-19-10-11-22-18(12-19)14-27-32-22/h3-14,16H,15H2,1-2H3,(H,27,32)(H,28,33)(H,29,30,31)

2.1.3 InChI Key

GKHIVNAUVKXIIY-UHFFFAOYSA-N

2.1.4 Canonical SMILES

CC(C)NC(=O)COC1=CC=CC(=C1)C2=NC3=CC=CC=C3C(=N2)NC4=CC5=C(C=C4)NN=C5

2.2 Other Identifiers

2.2.1 UNII

834YJF89WO

2.3 Synonyms

2.3.1 MeSH Synonyms

1. Belumosudil

2. Rezurock

2.3.2 Depositor-Supplied Synonyms

1. 911417-87-3

2. Slx-2119

3. Belumosudil

4. Kd-025

5. Kd025

6. Rock Inhibitor 2

7. Rezurock

8. Belumosudil [usan]

9. Slx 2119

10. Slx-2119 Free Base

11. Rock2 Inhibitor Kd025

12. 2-[3-[4-(1h-indazol-5-ylamino)quinazolin-2-yl]phenoxy]-n-propan-2-ylacetamide

13. Slx2119

14. 834yjf89wo

15. C26h24n6o2

16. Kd025 (slx-2119)

17. Acetamide, 2-(3-(4-(1h-indazol-5-ylamino)-2-quinazolinyl)phenoxy)-n-(1-methylethyl)-

18. 2-(3-(4-(1h-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-n-isopropylacetamide

19. 2-[3-[4-(1~{h}-indazol-5-ylamino)quinazolin-2-yl]phenoxy]-~{n}-propan-2-yl-ethanamide

20. 2-[3-[4-(1h-indazol-5-ylamino)-2-quinazolinyl]phenoxy]-n-(1-methylethyl)-acetamide

21. 2-[3-[4-[(1h-indazol-5-yl)amino]quinazolin-2-yl]phenoxy]-n-isopropylacetamide

22. Unii-834yjf89wo

23. Kinome_2597

24. Belumosudil [inn]

25. Belumosudil [who-dd]

26. Schembl878202

27. Gtpl9558

28. Chembl2005186

29. Dtxsid80238425

30. Bdbm322155

31. Bdbm435505

32. Bcp15921

33. Ex-a2314

34. Kd 025

35. Mfcd23098791

36. S7936

37. Who 11343

38. Zinc63298464

39. Slx-2119(kd-025)

40. Slx-2119; Kd-025

41. Us10570123, Example 232

42. Ccg-269256

43. Cs-0776

44. Sb16915

45. Ncgc00378903-01

46. Ncgc00378903-02

47. Ac-33057

48. As-35230

49. Hy-15307

50. Db-103511

51. Us10183931, Slx-2119

52. A855956

53. Q27269397

54. 2-(3-{4-[(1h-indazol-5-yl)amino]quinazolin-2-yl}phenoxy)-n-(propan-2-yl)acetamide

55. 2-[3-[4-(1h-indazol-5-ylamino)-2-quinazolinyl]phenoxy]-n-(1-methylethyl)acetamide

56. Icq

2.4 Create Date

2006-11-20

3 Chemical and Physical Properties

Molecular Formula	C₂₆H₂₄N₆O₂
Molecular Weight	452.5 g/mol
XLogP3	4.8
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	6
Rotatable Bond Count	7
Exact Mass	452.19607403 g/mol
Monoisotopic Mass	452.19607403 g/mol
Topological Polar Surface Area	105 Å²
Heavy Atom Count	34
Formal Charge	0
Complexity	678
Isotope Atom Count	0
Defined Atom Stereocenter Count	0
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

Belumosudil is indicated for the treatment of chronic graft-versus-host disease (GVHD) in adult and pediatric patients 12 years of age and older following failure of at least two other lines of systemic therapy.

5 Pharmacology and Biochemistry

5.1 Pharmacology

Belumosudil appears to inhibit several pro-fibrotic and pro-inflammatory processes in order to prevent and treat the damage incurred by graft-versus-host disease. Given its mechanism of action and findings in animal trials, belumosudil is considered to carry embryo-fetal toxicity and may cause significant harm to a developing fetus should a pregnant mother be exposed. Female patients of reproductive potential, or male patients with female partners of reproductive potential, should be advised to use effective contraception during treatment with belumosudil and for one week after the last dose.

5.2 MeSH Pharmacological Classification

Protein Kinase Inhibitors

Agents that inhibit PROTEIN KINASES. (See all compounds classified as Protein Kinase Inhibitors.)

5.3 ATC Code

L - Antineoplastic and immunomodulating agents

L04 - Immunosuppressants

L04A - Immunosuppressants

L04AA - Selective immunosuppressants

L04AA48 - Belumosudil

5.4 Absorption, Distribution and Excretion

Absorption

Following oral administration, the mean bioavailability of belumosudil is 64% and the median T_max at steady-state is 1.26 to 2.53 hours. As compared to administration in a fasted state, belumosudil C_max and AUC increased by 2.2 and 2 times, respectively, when administered with a high-fat, high-calorie meal.

Route of Elimination

Belumosudil is eliminated primarily in the feces. Following the administration of a radiolabeled oral dose of belumosudil in healthy subjects, approximately 85% of the radioactivity was recovered in the feces, 30% of which was unchanged parent drug, with less than 5% recovered in the urine.

Volume of Distribution

Following a single oral dose of belumosudil in healthy subjects, the mean geometric volume of distribution was 184 L.

Clearance

The mean clearance of belumosudil is 9.83 L/h.

5.5 Metabolism/Metabolites

The _in vitro_ metabolism of belumosudil occurs primarily via CYP3A4 and to a lesser extent by CYP2C8, CYP2D6, and UGT1A9. The specific metabolites generated by belumosudil metabolism remain unclear.

5.6 Biological Half-Life

The mean elimination half-life of belumosudil following oral administration is 19 hours.

5.7 Mechanism of Action

Chronic graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation in which the transplanted donor T-cells recognize the recipient's tissues as foreign and mount an immune response. During the conditioning regimen prior to stem cell transplantation (e.g. involving irradiation or chemotherapy) the host tissues can become damaged which results in downstream inflammatory responses and the generation of inflammatory mediators like TNF-alpha and IL-1. These cytokines increase the expression of host major histocompatibility (MHC) antigens and adhesion molecules which enhances the ability of mature donor T-cells to recognize these molecules. The activation of these donor T-cells results in the activation of mononuclear phagocytes, whose effector functions are triggered by stimulatory molecules generated by the damage incurred during the conditioning phase of treatment. Activated macrophages and cytotoxic T-lymphocytes begin to directly lyse target cells and/or cause their apoptosis, which eventually leads to local tissue damage and further inflammatory responses. Belumosudil is an inhibitor of Rho-associated coiled-coil kinase 2 (ROCK2), a protein that plays a vital role in the pathogenesis of immune and fibrotic diseases. The inhibition of ROCK2 has been shown to resolve immune dysregulation by down-regulating pro-inflammatory Th17 cells and up-regulating regulatory T-cells by manipulating the phosphorylation of STAT3 and STAT5.

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