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Chemistry

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Also known as: 223645-67-8, K-115 free base, K115 free base, Ripasudil [inn], Ripasudil free base, K-115 (free base)
Molecular Formula
C15H18FN3O2S
Molecular Weight
323.4  g/mol
InChI Key
QSKQVZWVLOIIEV-NSHDSACASA-N
FDA UNII
11978226XX

Ripasudil
Ripasudil, as hydrochloride hydrate (K-115), is a specifc Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor used for the treatment of glaucoma and ocular hypertension. It was first approved for treatment in Japan in September 2014. This medication is available in the form of a 0.4% eye drop solution under the brand name Glanatec. Ripasudil is a well tolerated medication that is used when other drugs have been proven to be non-effective or cannot be administered.
1 2D Structure

Ripasudil

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
4-fluoro-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline
2.1.2 InChI
InChI=1S/C15H18FN3O2S/c1-11-8-17-6-3-7-19(11)22(20,21)14-5-2-4-12-9-18-10-13(16)15(12)14/h2,4-5,9-11,17H,3,6-8H2,1H3/t11-/m0/s1
2.1.3 InChI Key
QSKQVZWVLOIIEV-NSHDSACASA-N
2.1.4 Canonical SMILES
CC1CNCCCN1S(=O)(=O)C2=CC=CC3=CN=CC(=C32)F
2.1.5 Isomeric SMILES
C[C@H]1CNCCCN1S(=O)(=O)C2=CC=CC3=CN=CC(=C32)F
2.2 Other Identifiers
2.2.1 UNII
11978226XX
2.3 Synonyms
2.3.1 MeSH Synonyms

1. Glanatec

2. K-115

3. K115 Compound

2.3.2 Depositor-Supplied Synonyms

1. 223645-67-8

2. K-115 Free Base

3. K115 Free Base

4. Ripasudil [inn]

5. Ripasudil Free Base

6. K-115 (free Base)

7. Chembl3426621

8. 4-fluoro-5-[[(2s)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline

9. 11978226xx

10. (s)-4-fluoro-5-((2-methyl-1,4-diazepan-1-yl)sulfonyl)isoquinoline

11. 1h-1,4-diazepine, 1-((4-fluoro-5-isoquinolinyl)sulfonyl)hexahydro-2-methyl-, (2s)-

12. Isoquinoline, 4-fluoro-5-(((2s)-hexahydro-2-methyl-1h-1,4-diazepin-1-yl)sulfonyl)-

13. Unii-11978226xx

14. K 115 Free Base

15. Ripasudil [mi]

16. Ripasudil [who-dd]

17. Schembl31542

18. Gtpl10423

19. Chebi:136046

20. Dtxsid001025609

21. Bcp11083

22. Ex-a3647

23. Zinc3940873

24. Bdbm50087135

25. Hy-15685a

26. Mfcd28291829

27. Nsc800869

28. Cs-3402

29. Db13165

30. Nsc-800869

31. Ncgc00496843-01

32. Ac-36873

33. As-35170

34. K-115 (ripasudil Hydrochloride Dihydrate)

35. Q21098890

36. (s)-(-)-1-(4-fluoro-5-isoquinolinesulfonyl)-2-methyl-1,4-homopiperazine

37. 4-fluoro-5-[[(2s)-2beta-methylhexahydro-1h-1,4-diazepine-1-yl]sulfonyl]isoquinoline

2.4 Create Date
2006-10-25
3 Chemical and Physical Properties
Molecular Weight 323.4 g/mol
Molecular Formula C15H18FN3O2S
XLogP31.5
Hydrogen Bond Donor Count1
Hydrogen Bond Acceptor Count6
Rotatable Bond Count2
Exact Mass323.11037616 g/mol
Monoisotopic Mass323.11037616 g/mol
Topological Polar Surface Area70.7 Ų
Heavy Atom Count22
Formal Charge0
Complexity482
Isotope Atom Count0
Defined Atom Stereocenter Count1
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Drug Indication

Ripasudil has been proven to be effective in the twice daily treatment of glaucoma and ocular hypertension. It is currently in studies to be approved for both diabetic retinopathy and diabetic macular oedema.


Treatment of corneal dystrophy


5 Pharmacology and Biochemistry
5.1 Pharmacology

Ripasudil has high intraocular permeability and works by decreasing intraocular pressure (IOP) in a dose-dependent manner and increasing flow facility. The maximum reduction of IOP occurs after 1 to 2 hours.


5.2 ATC Code

S - Sensory organs

S01 - Ophthalmologicals

S01E - Antiglaucoma preparations and miotics

S01EX - Other antiglaucoma preparations

S01EX07 - Ripasudil


5.3 Absorption, Distribution and Excretion

Route of Elimination

Riapsudil is cleared by the kidneys at a rate of 7.112L/h.


Clearance

Ripasudil has a renal clearance of 7.112 L/h.


5.4 Biological Half-Life

The half life of Ripasudil is 0.455 hrs.


5.5 Mechanism of Action

Ripasudil is a highly selective and potent Rho-associated coiled/coil-containing kinase protein (ROCK) inhibitor. Rho-kinase (ROCK) is an effector protein of Rho which binds with Rho to form a Rho/Rho-kinase complex. This complex then regulates many physiological functions including smooth muscle contractions, chemotaxis, neural growth and gene expression. ROCK comes in 2 isoforms: ROCK-1 and ROCK-2 and these two isoforms are distributed widely in our tissues including ocular tissues such as the iris, retina, trabecular meshwork and ciliary muscles. Atypical regulation of ROCK levels is involved in the pathogenesis of diseases such as glaucoma, ocular hypertension, cataracts and other retinal disorders. Ripasudil acts as very highly selective and potent inhibitor with an IC50 of Ripasudil with ROCK-1 of 0.051 umol/L and with ROCK-2 of 0.019 umol/L. ROCK inhibitors have efficacy in reducing IOP by acting on the trabecular meshwork in the eye directly to increase conventional outflow through the Schlemms canal. Ripasudil will inhibit ROCK and induce cytoskeletal changes including the retraction and rounding of cell bodies and cause disruption of actin bundles in this trabecular meshwork. This can reduce the compaction of trabecular meshwork tissue and eventually result in increased aqueous outflow in the eye and reduced resistance to fluid flow. Thus, Ripasudil is effective by inducing cytoskeletal changes which are depending on ROCK inhibition. Ripasudil decreases IOP by increasing outflow facility along with modulating the behavior of trabecular meshwork cells and Schlemms canal endothelial (SCE) cell permeability along with a disruption of the tight junction. When Ripasudil is used in combination with prostaglandin analogues it results in increased uveoscleral outflow and when used in combination with beta blockers it results in reduced aqueous production.


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01-Oct-2022
01-Oct-2022
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