Identification
- Summary
Ripasudil is a rho kinase inhibitor indicated to treat ocular hypertension and open-angle glaucoma.
- Generic Name
- Ripasudil
- DrugBank Accession Number
- DB13165
- Background
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.
- Type
- Small Molecule
- Groups
- Experimental
- Structure
Structure for Ripasudil (DB13165)
- Weight
- Average: 323.39
Monoisotopic: 323.110376169 - Chemical Formula
- C15H18FN3O2S
- Synonyms
- Ripasudil
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.
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- Contraindications & Blackbox Warnings
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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.
Target Actions Organism URho-associated protein kinase 1 inhibitorHumans URho-associated protein kinase 2 inhibitorHumans - 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.
- Adverse Effects
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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.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.Not Available
- Food Interactions
- Not Available
Products
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Ingredient UNII CAS InChI Key Ripasudil hydrochloride dihydrate 016TTR32QF 887375-67-9 CMDJNMACGABCKQ-XVSRHIFFSA-N
Categories
- ATC Codes
- S01EX07 — Ripasudil
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- 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
- 1,4-diazepane / Amine / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Azacycle / Benzenoid / Diazepane / Heteroaromatic compound / Hydrocarbon derivative show 15 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 11978226XX
- CAS number
- 223645-67-8
- 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
References
- General References
- 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. [Article]
- Garnock-Jones KP: Ripasudil: first global approval. Drugs. 2014 Dec;74(18):2211-5. doi: 10.1007/s40265-014-0333-2. [Article]
- 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. [Article]
- NPRA Product Information: Glanatec (ripasudil hydrochloride) ophthalmic solution [Link]
- External Links
- PubChem Compound
- 9863672
- PubChem Substance
- 347829272
- ChemSpider
- 8039366
- BindingDB
- 50087135
- ChEBI
- 136046
- ChEMBL
- CHEMBL3426621
- ZINC
- ZINC000003940873
- Wikipedia
- Ripasudil
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Recruiting Treatment Fuchs' Endothelial Dystrophy 1 3 Active Not Recruiting Treatment Corneal Edema After Cataract Surgery 1 3 Completed Treatment Ocular Hypertension / Ocular Hypertension, Primary Open-angle Glaucoma (POAG) 1 3 Recruiting Treatment Fuchs 1 3 Recruiting Treatment Fuchs / Fuchs' Dystrophy / Fuchs' Endothelial Dystrophy 1 2 Recruiting Treatment Fuchs' Endothelial Dystrophy 1 2 Unknown Status Treatment Cornea Guttata / Endothelial Cell Loss, Corneal / Endothelial Corneal Dystrophy / Fuchs' Dystrophy / Fuchs' Endothelial Dystrophy 1 1 Recruiting Treatment Bullous Keratopathy / Corneal Edema / Corneal Edema Pseudophakic / Endothelial Corneal Dystrophy / Endothelial Dysfunction / Fuchs' Dystrophy / Fuchs' Endothelial Dystrophy / Pseudophakic Bullous Keratopathy 1 1, 2 Completed Treatment Retinopathy of Prematurity (ROP) 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Solution / drops Ophthalmic Solution / drops Ophthalmic 4 mg/1ml Solution Ophthalmic 0.4 g/100ml - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.3 mg/mL ALOGPS logP 0.72 ALOGPS logP 0.88 Chemaxon logS -3 ALOGPS pKa (Strongest Basic) 8.2 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 62.3 Å2 Chemaxon Rotatable Bond Count 1 Chemaxon Refractivity 82.56 m3·mol-1 Chemaxon Polarizability 31.25 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- 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
- Humans
- 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 at January 20, 2017 21:20 / Updated at June 05, 2021 09:12