Identification

Name
Ripasudil
Accession Number
DB13165
Type
Small Molecule
Groups
Experimental
Description

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.

Structure
Thumb
Synonyms
Not Available
Product Ingredients
IngredientUNIICASInChI Key
Ripasudil hydrochloride dihydrate016TTR32QF887375-67-9CMDJNMACGABCKQ-XVSRHIFFSA-N
Categories
UNII
11978226XX
CAS number
223645-67-8
Weight
Average: 323.39
Monoisotopic: 323.110376169
Chemical Formula
C15H18FN3O2S
InChI Key
QSKQVZWVLOIIEV-NSHDSACASA-N
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
IUPAC Name
4-fluoro-5-{[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl}isoquinoline
SMILES
C[C@H]1CNCCCN1S(=O)(=O)C1=C2C(F)=CN=CC2=CC=C1

Pharmacology

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.

Pharmacodynamics

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.

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 Schlemm’s 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 Schlemm’s 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.

TargetActionsOrganism
URho-associated protein kinase 1
inhibitor
Human
URho-associated protein kinase 2
inhibitor
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding

The plasma protein binding rate of Ripasudil is 55.4-59.8%

Metabolism
Not Available
Route of elimination

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

Half life

The half life of Ripasudil is 0.455 hrs.

Clearance

Ripasudil has a renal clearance of 7.112 L/h.

Toxicity

The most frequent adverse effect of Ripasduil is mild to moderately severe conjunctival hyperemia which was found to cease spontaneously within hours. Mild conjunctival follicles were also reported which also were spontaneously resolved. Other adverse effects include ocular irritation, an abnormal sensation in the eye and conjunctival haemorrhage.

Ripasudil has not been found to have any effects to other receptors and enzymes including serine-threonine protein kinases.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Kaneko Y, Ohta M, Inoue T, Mizuno K, Isobe T, Tanabe S, Tanihara H: Effects of K-115 (Ripasudil), a novel ROCK inhibitor, on trabecular meshwork and Schlemm's canal endothelial cells. Sci Rep. 2016 Jan 19;6:19640. doi: 10.1038/srep19640. [PubMed:26782355]
  2. Garnock-Jones KP: Ripasudil: first global approval. Drugs. 2014 Dec;74(18):2211-5. doi: 10.1007/s40265-014-0333-2. [PubMed:25414122]
  3. Tanihara H, Inoue T, Yamamoto T, Kuwayama Y, Abe H, Araie M: Phase 1 clinical trials of a selective Rho kinase inhibitor, K-115. JAMA Ophthalmol. 2013 Oct;131(10):1288-95. doi: 10.1001/jamaophthalmol.2013.323. [PubMed:23787820]
External Links
PubChem Compound
9863672
PubChem Substance
347829272
ChemSpider
8039366
ChEBI
136046
ChEMBL
CHEMBL3426621
Wikipedia
Ripasudil

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4RecruitingTreatmentFuchs' Endothelial Dystrophy1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.3 mg/mLALOGPS
logP0.72ALOGPS
logP0.88ChemAxon
logS-3ALOGPS
pKa (Strongest Basic)8.2ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area62.3 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity82.56 m3·mol-1ChemAxon
Polarizability31.25 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as isoquinolines and derivatives. These are aromatic polycyclic compounds containing an isoquinoline moiety, which consists of a benzene ring fused to a pyridine ring and forming benzo[c]pyridine.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Isoquinolines and derivatives
Sub Class
Not Available
Direct Parent
Isoquinolines and derivatives
Alternative Parents
1,4-diazepanes / Pyridines and derivatives / Organosulfonamides / Benzenoids / Aryl fluorides / Sulfonyls / Heteroaromatic compounds / Dialkylamines / Azacyclic compounds / Organofluorides
show 2 more
Substituents
Isoquinoline / 1,4-diazepane / Diazepane / Aryl fluoride / Aryl halide / Pyridine / Organosulfonic acid amide / Benzenoid / Heteroaromatic compound / Organosulfonic acid or derivatives
show 15 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Protein serine/threonine kinase activity
Specific Function
Protein kinase which is a key regulator of actin cytoskeleton and cell polarity. Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesio...
Gene Name
ROCK1
Uniprot ID
Q13464
Uniprot Name
Rho-associated protein kinase 1
Molecular Weight
158173.545 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Structural molecule activity
Specific Function
Protein kinase which is a key regulator of actin cytoskeleton and cell polarity. Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesio...
Gene Name
ROCK2
Uniprot ID
O75116
Uniprot Name
Rho-associated protein kinase 2
Molecular Weight
160898.555 Da

Drug created on January 20, 2017 14:20 / Updated on October 01, 2018 16:49