Ripasudil

Ripasudil (trade name Glanatec), a derivative of fasudil, is a rho kinase inhibitor drug (previously known as K-115)[1] used for the treatment of glaucoma and ocular hypertension.

Ripasudil
Clinical data
Trade namesGlanatec
Other namesK-115
Routes of
administration		Topical (ophthalmic solution)
Identifiers
PubChem CID
ChemSpider
KEGG
Chemical and physical data
FormulaC15H18FN3O2S
Molar mass323.39 g·mol−1
3D model (JSmol)

Pharmacology

Pharmacodynamics

Ripasudil's mechanism of action affects intraocular pressure, or IOP, "by directly acting on the trabecular meshwork, thereby increasing conventional outflow through the Schlemm’s canal." [2] More simply, it is an "out-flow" drug that reduces IOP by stimulating the movement of aqueous humour from the ciliary body away from the eye.[3] It is a selective rho-associated coiled-coil-containing protein kinase 1 (ROCK1) inhibitor, where ROCK1 is "an important downstream effector of Rho guanosine trisphosphates (GTP),"[2] proteins that are significant in the contractile control of smooth muscle tissue. The S configuration at the 2-position on the 1,4-diazepane ring of Ripasudil is what gives the drug its characteristic effect.[4]

Ripasudil was originally developed from fasudil, as both compounds share the same core structure of 5-(1,4-diazepan-1-ylsulfonyl)isoquinoline. Fasudil was already recognized as a potent Rho-kinase inhibitor, but after exploring the chemical derivatives of fasudil, developers observed that the incorporation of a fluorine atom at the C4 position of isoquinoline moiety and the chiral attachment of a methyl group to the C2’ position of 1,4-diazepane moiety dramatically improved the pharmacological action. In short, "ripasudil showed much more potent and selective Rho-kinase inhibitory activity than fasudil".[5]

According to a report submitted to the Japanese Pharmaceuticals and Medical Devices Agency regarding Glanatec, ripasudil hydrochloride hydrate showed no binding affinity for receptors of the adrenergic, angiotensin II, endothelin, glutamate, histamine, muscarinic, or prostanoid variety. This lack of affinity also applies to Ca2+ and K+ channels, carbonic anhydrase, and HMG-CoA reductase.[6]

Toxicity information is compiled in the following tables.

Single dose toxicity[6][7]
Delivery route Gender specificity
Specimen Oral I.V. Male Female
Mouse ALD 122.55 mg/kg >20.42 mg/kg N/A
Rat ALD 87.70 mg/kg 20.42 mg/kg N/A
Dog MTD N/A < 25 mg/kg 18 mg/kg
Repeated dose toxicity[6][7]
Specimen Dose regimen Study length NOAEL Comments
Rabbits Twice daily in right eye 26 weeks 1.0% No mortality at all doses. After ocular administration, symptoms included hypermia of the bulbar and papebral conjunctiva, white spots in the lens.
Dogs Once a day in right eye and orally 13 weeks 2.0% in eye, 7.5 mg/kg/day by mouth No mortality observed.
Monkey Once a day in right eye 52 weeks 2.0% Mortalities observed.
Rats Once a day orally 4 weeks 10 or 30 mg/kg/day in males and females Mortality observed at oral administration of 90 mg/kg/day.

Ripasudil had no effect on respiratory or neurological function. Although no carcinogenicity studies were performed on the drug, developers believed it to be non-carcinogenic due to its rapid elimination and therefore lack of accumulation in tissue, as well as the lack of inflammatory response in the eye post-administration.[6]

Pharmacokinetics

Ripasudil achieves a half-life of 0.49 to 0.73 hours in humans and is predominantly excreted in the urine.

History

Ripasudil (in the form of ripasudil hydrochloride hydrate) was approved by the PMDA of Japan on September 26, 2014. Glanatec, the trade name of the approved formulation, takes the form of an eye drop solution of 0.4% ripasudil, equivalent to 4 g of ripasudil per 1000 mL of solution. The solution is developed, marketed, and distributed by Kowa Pharmaceuticals, but the compound itself was discovered by D. Western Therapeutics Institute,[2] a company who specializes in protein kinase inhibitory compounds.[8]

In September 2002, Kowa Company entered a licensing agreement with D. Western Therapeutics Institute, Inc. with regard to global rights of ripasudil.[2] Under this agreement, D. Western Therapeutics Institute is eligible to receive milestone payments from Kowa.

Kowa Company was issued a US patent (No. 8,193,193, entitled ‘‘Agent for prevention or treatment of glaucoma’’) on June 5, 2012 for the use of ripasudil in patients with glaucoma.[9] As of June 25th, 2013, Glanatec is a registered U.S. federal trademark attributed to Kowa.[10]

Additional Medical uses

Ripasudil has been proven to have additional medical uses aside from reducing IOP and alleviating symptoms of glaucoma and ocular hypertension. For example, in March 2016 the drug was shown to promote corneal endothelial cell (CEC) proliferation in cultured human cells as well as wound healing and endothelium regeneration in a rabbit wound model.[11] Experimenters believed that these characteristics could prevent or improve the CEC density drop associated with cataract surgery or corneal trauma. This would prevent an array of symptoms including general haziness, edema of the cornea, or keratopathy, and would generally improve the recovery of a post-operation patient.

As of 2016, Ripasudil has also been shown to prevent excessive scarring after glaucoma filtration surgery by attenuating the activation of conjunctival fibroblasts.[12] The drug was also under clinical review for its ability to alleviate symptoms of diabetic retinopathy in early 2014.[2]

Adverse effects

The most common adverse event reported in phase III trials for ripasudil was mild conjunctival hyperemia. Additionally, up to 3.8% of trial participants reported ocular irritation after using the drug with up to 5.7% reporting conjunctival hemorrhage. There were several cases of “abnormal sensation in the eye” reported.[13] On a cellular level, Okumura et al. found that ripasudil produced "guttae-like" formations in ocular endothelial cells post-administration, which was attributed to, "protrusion formation along intracellular borders caused by the reduction in actomyosin contractility of the CECs." [14] However, these morphological changes to the eye were considered transient and therefore quick to reverse, unlike symptoms Fuchs endothelial corneal dystrophy, a disorder for which these short-lived symptoms could be mistaken.

References
  1. Tanihara H, Inoue T, Yamamoto T, Kuwayama Y, Abe H, Suganami H, Araie M (June 2015). "Intra-ocular pressure-lowering effects of a Rho kinase inhibitor, ripasudil (K-115), over 24 hours in primary open-angle glaucoma and ocular hypertension: a randomized, open-label, crossover study". Acta Ophthalmologica. 93 (4): e254-60. doi:10.1111/aos.12599. PMID 25487877.
  2. Garnock-Jones KP (December 2014). "Ripasudil: first global approval". Drugs. 74 (18): 2211–5. doi:10.1007/s40265-014-0333-2. PMID 25414122.
  3. "GLANATEC® ophthalmic solution 0.4% | D.Western Therapeutics Institute, Inc". D.Western Therapeutics Institute, Inc. Retrieved 2016-11-21.
  4. Isobe T, Mizuno K, Kaneko Y, Ohta M, Koide T, Tanabe S (August 2014). "Effects of K-115, a rho-kinase inhibitor, on aqueous humor dynamics in rabbits". Current Eye Research. 39 (8): 813–22. doi:10.3109/02713683.2013.874444. PMID 24502505.
  5. Sharma R (2016-08-04). "ayurajan: Ripasudil | Kinase Inhibitor | ROCK Inhibitor | Treatment of Glaucoma | Treatment of Ocular Hypertension". ayurajan. Retrieved 2016-11-21.
  6. "新薬の承認に関する情報". www.pmda.go.jp. Retrieved 2016-11-21.
  7. "Ripasudil Hydrochloride Hydrate - Pharmacodia". www.pharmacodia.com. Retrieved 2016-11-21.
  8. "Drug Discovery and Development Business | D.Western Therapeutics Institute, Inc". D.Western Therapeutics Institute, Inc. Retrieved 2016-11-21.
  9. US 8193193, Mizuno K, Mastumoto J, "Agent for prevention or treatment of glaucoma", published 7 May 2009, assigned to Kowa Company
  10. "Apply for a Trademark. Search a Trademark". trademarkia.com. Retrieved 2016-11-21.
  11. Okumura N, Okazaki Y, Inoue R, Kakutani K, Nakano S, Kinoshita S, Koizumi N (March 2016). "Effect of the Rho-Associated Kinase Inhibitor Eye Drop (Ripasudil) on Corneal Endothelial Wound Healing". Investigative Ophthalmology & Visual Science. 57 (3): 1284–92. doi:10.1167/iovs.15-18586. PMID 26998714.
  12. Futakuchi A, Inoue T, Fujimoto T, Inoue-Mochita M, Kawai M, Tanihara H (August 2016). "The effects of ripasudil (K-115), a Rho kinase inhibitor, on activation of human conjunctival fibroblasts". Experimental Eye Research. 149: 107–115. doi:10.1016/j.exer.2016.07.001. PMID 27394186.
  13. Tanihara, H (2014). "Phase 3 randomized clinical studies of a Rho kinase inhibitor, K-115, in combination with timolol or latanoprost in primary open-angle glaucoma and ocular hypertension". World Ophthalmology Congress.
  14. Okumura N, Okazaki Y, Inoue R, Nakano S, Fullwood NJ, Kinoshita S, Koizumi N (November 2015). "Rho-Associated Kinase Inhibitor Eye Drop (Ripasudil) Transiently Alters the Morphology of Corneal Endothelial Cells". Investigative Ophthalmology & Visual Science. 56 (12): 7560–7. doi:10.1167/iovs.15-17887. PMID 26618648.
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