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Grapiprant

Grapiprant

Synopsis, Chemistry

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Also known as: 415903-37-6, Cj-023423, Aat-007, Cj 023423, Rq-7, Rq-00000007

Molecular Formula

C₂₆H₂₉N₅O₃S

Molecular Weight

491.6 g/mol

InChI Key

HZVLFTCYCLXTGV-UHFFFAOYSA-N

FDA UNII

J9F5ZPH7NB

Grapiprant is an orally bioavailable antagonist of the prostaglandin E receptor subtype 4 (EP4), with potential analgesic, immunomodulating and antineoplastic activities. Upon administration of grapiprant, this agent selectively binds to and inhibits the binding of prostaglandin E2 (PGE2) and prevents the activation of the EP4 receptor. This inhibits PGE2-EP4 receptor-mediated signaling and prevents proliferation in tumor cells in which the PGE2-EP4 signaling pathway is over-activated. In addition, EP4 receptor inhibition modulates the immune system by preventing both interleukin-23 (IL-23) production and the IL-23-mediated expansion of Th17 cells. As EP4 is expressed by peripheral sensory neurons, blockade of EP4-mediated signaling may induce an analgesic effect. EP4, a prostanoid receptor subtype, is a G protein-coupled receptor that is expressed in certain types of cancers; it promotes tumor cell proliferation and invasion.

1 2D Structure

Grapiprant

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

1-[2-[4-(2-ethyl-4,6-dimethylimidazo[4,5-c]pyridin-1-yl)phenyl]ethyl]-3-(4-methylphenyl)sulfonylurea

2.1.2 InChI

InChI=1S/C26H29N5O3S/c1-5-24-29-25-19(4)28-18(3)16-23(25)31(24)21-10-8-20(9-11-21)14-15-27-26(32)30-35(33,34)22-12-6-17(2)7-13-22/h6-13,16H,5,14-15H2,1-4H3,(H2,27,30,32)

2.1.3 InChI Key

HZVLFTCYCLXTGV-UHFFFAOYSA-N

2.1.4 Canonical SMILES

CCC1=NC2=C(N1C3=CC=C(C=C3)CCNC(=O)NS(=O)(=O)C4=CC=C(C=C4)C)C=C(N=C2C)C

2.2 Other Identifiers

2.2.1 UNII

J9F5ZPH7NB

2.3 Synonyms

2.3.1 MeSH Synonyms

1. 1-(2-(4-(2-ethyl-4,6-dimethylimidazo(4,5-c)pyridin-1-yl)phenyl)ethyl)-3-(4-methylphenyl)sulfonylurea

2. Aat-007

3. Cj 023,423

4. Cj 023423

5. Cj-023

6. Cj-023,423

7. Cj-023423

8. Mr-10a7

9. Mr10a7

10. N-(((2-(4-(2-ethyl-4,6-dimethyl-1h-imidazo(4,5-c)pyridin-1-yl) Phenyl)ethyl)amino)carbonyl)-4-methylbenzenesulfonamide

11. Rq-00000007

12. Rq-7

2.3.2 Depositor-Supplied Synonyms

1. 415903-37-6

2. Cj-023423

3. Aat-007

4. Cj 023423

5. Rq-7

6. Rq-00000007

7. Mr-10a7

8. Cj-023,423

9. N-((4-(2-ethyl-4,6-dimethyl-1h-imidazo[4,5-c]pyridin-1-yl)phenethyl)carbamoyl)-4-methylbenzenesulfonamide

10. Cj-023

11. Mr10a7

12. J9f5zph7nb

13. Grapiprant (cj-023423)

14. 706802-34-8

15. Cj-023423;rq-00000007;aat-007

16. 1-[2-[4-(2-ethyl-4,6-dimethylimidazo[4,5-c]pyridin-1-yl)phenyl]ethyl]-3-(4-methylphenyl)sulfonylurea

17. Benzenesulfonamide, N-(((2-(4-(2-ethyl-4,6-dimethyl-1h-imidazo(4,5-c)pyridin-1-yl)phenyl)ethyl)amino)carbonyl)-4-methyl-

18. Grapiprant [usan:inn]

19. Unii-j9f5zph7nb

20. 1-(2-(4-(2-ethyl-4,6-dimethylimidazo(4,5-c)pyridin-1-yl)phenyl)ethyl)-3-(4-methylphenyl)sulfonylurea

21. N-(((2-(4-(2-ethyl-4,6-dimethyl-1h-imidazo(4,5-c)pyridin-1-yl)phenyl)ethyl)amino)carbonyl)-4-methylbenzenesulfonamide

22. N-[([2-[4-(2-ethyl-4,6-dimethyl-1h-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl]amino)carbonyl]-4-methylbenzenesulfonamide

23. Grapiprant [mi]

24. Grapiprant [inn]

25. Grapiprant (usan/inn)

26. Grapiprant [usan]

27. Grapiprant [who-dd]

28. Schembl120428

29. Gtpl5858

30. Grapiprant [green Book]

31. Chembl3039498

32. Dtxsid60194419

33. Bcp20570

34. Ex-a2544

35. Bdbm50107283

36. S6694

37. Zinc38228051

38. Akos030526811

39. Aat-007cj-023423

40. Cs-5392

41. Db12836

42. Sb18902

43. Ac-36123

44. As-77380

45. Hy-16781

46. A15964

47. D10638

48. D83673

49. A900379

50. Q27077852

51. B0084-470919

52. Cj-023423; Rq-00000007; Aat-007

53. Grapiprant; Rq-00000007; Aat-007; Cj-023423

54. 2-ethyl-4,6-dimethyl-1-(4-(2-(((((4-methylphenyl)sulfonyl)amino)carbonyl)amino)ethyl)phenyl)-1h-imidazo(4,5-c)pyridine

55. Benzenesulfonamide,n-[[[2-[4-(2-ethyl-4,6-dimethyl-1h-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl]amino]carbonyl]-4-methyl-

56. N-(((2-(4-(2-ethyl-4,6-dimethyl-1h-imidazo(4,5-c)pyridin-1-yl)phenyl)ethyl)amino)carbonyl)-4-methyl-benzenesulfonamide

2.4 Create Date

2006-10-26

3 Chemical and Physical Properties

Molecular Formula	C₂₆H₂₉N₅O₃S
Molecular Weight	491.6 g/mol
XLogP3	4.6
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	5
Rotatable Bond Count	7
Exact Mass	491.19911098 g/mol
Monoisotopic Mass	491.19911098 g/mol
Topological Polar Surface Area	114 Å²
Heavy Atom Count	35
Formal Charge	0
Complexity	802
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

The effects of grapiprant have been investigated in the area of analgesia and anti-inflammation due to the effects that have been reported about this molecule. This molecule has been approved and widely accepted to be used in veterinary for pain reduction in arthritis. In humans, it has been researched to be used in the control of pain and inflammation associated with osteoarthritis. The effect of grapiprant can be explained through the function of prostaglandin E2 (PGE2) which is a key mediator of swelling redness and pain which are classic signs of inflammation. The effect of PGE2 results from its action through four receptor EP1, EP2, EP3 and EP4 from which the EP4 is the primary mediator of PGE2-driven inflammation.

For the treatment of pain associated with mild to moderate osteoarthritis in dogs.

5 Pharmacology and Biochemistry

5.1 Pharmacology

Preclinical studies have shown that grapiprant is very effective to reduce acute and chronic pain and inflammation. The effect of grapiprant seems to be dose-dependent and it is comparable to the effect of rofecoxib and piroxicam. The effects of grapiprant have been reported to be effective in the relief from arthritic pain in canine patients.

5.2 ATC Code

QM01AX92

5.3 Absorption, Distribution and Excretion

Absorption

Studies in animals (horse) have shown the presence of a concentration >0.005 ng/ml in serum 72 hours after initial administration of a dose of 2 mg/kg. It is rapidly absorbed and the reported Cmax in this reports was 31.9 ng/ml in a Tmax of 1.5 hours and AUC of 2000 ng.hr/ml. In the case of bioavailability, grapiprant presents a mean bioavailability of 39%. The bioavailability, time for peak concentration and maximal concentration has been reported to be significantly reduced after food.

Route of Elimination

Following an oral dose, the majority of the dose an within the first 72 hours. Studies in animals (horse) have shown the presence of a concentration >0.005 ng/ml in urine 96 hours after initial administration of a dose of 2 mg/kg. From the excreted dose, 55%, 15% and 19% of the administered dose is excreted in bile, urine, and feces respectively.

Volume of Distribution

The reported volume of distribution in animal studies (cats) was reported to be 918 ml/kg.

Clearance

The reported clearance rate in animal studies (cats) was reported to be 173.2 ml/hr.kg.

5.4 Metabolism/Metabolites

_In vitro_ studies with dog microsomes have reported the identification of four metabolites, an N-deamination metabolite which is the major metabolite in urine and feces, two hydroxylated metabolites and one N-oxidation metabolite.

5.5 Biological Half-Life

The reported elimination half-life in animal studies (horse) is of 5.86 hours.

5.6 Mechanism of Action

Grapiprant is an EP4 prostaglandin receptor antagonist and thus the activity of this drug is thought to be completely related to the selective blockade of this receptor. It binds to human and other mammals EP4 prostaglandin receptor with high affinity without interfering with other prostaglandin pathways which are important for a variety of physiological functions. The binding of grapiprant blocks PGE2 binding and hence its biological effect related to the signaling pain and inflammation cascade. Grapiprant has been accepted very greatly in veterinary as its mechanism of action is a targeted approach to pain management by not having any interaction with the production of prostanoids and thus, by not interacting with other prostaglandin receptor pathways.