Thursday, August 4, 2016

Ripasudil | Kinase Inhibitor | ROCK Inhibitor | Treatment of Glaucoma | Treatment of Ocular Hypertension

Ripasudil [(S)-4-Fluoro-5-[(2-methyl-1,4-diazepan-1-yl)sulfonyl]isoquinoline] is a small molecule, highly potent and selective Rho-associated coiled coil-containing protein (ROCK) kinase inhibitor having the (S)-2-methyl-1,4-diazepane moiety. It was developed as promising candidate for the treatment of ocular hypertension with intraocular pressure-lowering activity and neuroprotection of retinal ganglion cells injured in glaucoma. The S configuration at the 2-position on the 1,4-diazepane ring of Ripasudil plays the pivotal role for expressing the physiological feature [1].

Ripasudil: 2D and 3D Structure

Ripasudil has been developed from Fasudil. Both compounds have the same core structure of 5-(1,4-diazepan-1-ylsulfonyl)isoquinoline. Fasudil has been recognized as a potent Rho-kinase inhibitor and clinically used for the treatment of cerebral vasospasm. After exploring the chemical derivatives of Fasudil, the incorporation of fluorine atom at C4 position of isoquinoline moiety and the chiral attachment of the methyl group at C2’ position of 1,4-diazepane moiety dramatically improved the pharmacological action. Ripasudil showed much more potent and selective Rho-kinase inhibitory activity than Fasudil and would be potentially expected to cure the Cerebral Vascular Disorder. Especially, it is noteworthy that Ripasudil is effective on the ocular hypertension with intraocular pressure (IOP)-lowering activity and neuroprotection of retinal ganglion cells injured in glaucoma. 

A 0.4% ophthalmic solution of Ripasudil was approved in Japan in September 2014 for the treatment of glaucoma and ocular hypertension when other therapeutic drugs are not effective or cannot be administered, at a dosage of 1 drop in the eye, twice daily.

Glaucoma and ROCK Inhibitors

Glaucoma is a disease that primarily damages the optic nerve head, which causes characteristic visual field loss and can eventually lead to blindness. The disease can be divided into two broad categories, open-angle and angle-closure (closed-angle) glaucoma, based on the appearance of the anterior chamber angle. The most common form of the disease is primary open-angle glaucoma (POAG), and chronically elevated intraocular pressure (IOP) occurs as a result of pathologically increased resistance to the drainage of aqueous humor through the outflow pathways.
The level of IOP is a risk factor for progression not only in POAG patients but also in normal tension glaucoma (NTG) patients, and it is therefore very important to reduce the IOP for glaucoma therapy.
Currently, available anti-glaucoma drugs are classified into two types-the first type decreases aqueous humor production and includes β-adrenergic blockers and carbonic anhydrase inhibitors, while the second class enhances uveoscleral outflow and includes prostaglandin analogs.
The trabecular meshwork, which is located in the anterior chamber angle, is responsible for draining the aqueous humor from the anterior chamber for conventional outflow, and is an ideal target for the effective management of IOP in patients. ROCK (Rho-associated coiled coil-containing protein kinase) is a serine/threonine kinase that serves as an important downstream effector of Rho GTPase, and plays a critical role in regulating the contractile tone of smooth muscle tissues in a calcium independent manner. ROCK has two isoforms (ROCK1 and ROCK2), both of which are expressed in the human trabecular meshwork and ciliary muscle cells.

Ripasudil as Kinase Inhibitor

Ripasudil showed potent and selective inhibitory effects on ROCKs. The 50% inhibitory concentration (IC50) of Ripasudil for ROCK 2 (0.019 uM) was 2.68 times lower (higher inhibitory effect) than that for ROCK 1 (0.051 uM). In addition, the IC50s of Ripasudil for PKACα, PKC, and CaMKIIα (2.1, 2.7 and 0.37 uM) were 111, 1420, and 19.5 times higher than that for ROCK 2, respectively [1].

Common name: K 115; K-115; K115; Ripasudil hydrochloride hydrate
Trademarks: Glanatec
Molecular Formula: C15H18FN3O2S
CAS Registry Number: 223645-67-8; 887375-67-9 (HCl Dihydrate)
CAS Name: 4-fluoro-5-{[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl}isoquinoline
Molecular Weight: 323.39
SMILES: O=S(=O)(c2c1c(F)cncc1ccc2)N3[C@H](CNCCC3)C
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
Mechanism of Action: Rho-associated kinase inhibitor; Kinase Inhibitor; ROCK Inhibitor
Activity: Treatment of Glaucoma; Treatment of Ocular Hypertension; Antineovascularisation Agents; Antiglaucoma Preparations and Miotics
Status: Launched 2014 (Japan)
Chemical Class: Azepines; Isoquinolines; Small-Molecules; Sulphonamides; Fluorine containing
Originator: Kowa Company, Ltd/D. Western Therapeutics Institute, Inc.

Ripasudil Synthesis
WO2012026529A1: The patent reports multi-kilogram synthesis of Ripasudil. 


Final Synthesis:


Experimental: 1H-NMR (DMSO-d6) δ: 1.20 (3H, d, J = 6.6 Hz), 1.98-2.07 (2H, m), 3.06-3.16 (1H, m), 3.22-3.31 (2H, m), 3.35 (4H, s), 3.44 (1H, dd, J = 14.1, 4.4 Hz), 3.59-3.74 (2H, m), 4.37-4.47 (1H, m), 7.93 (1H, t, J = 7.8 Hz), 8.32 (1H, d, J = 7.8 Hz), 8.54-8.60 (1H, m), 8.72 (1H, d, J = 4.9 Hz), 9.39 (1H, s), 9.51 (2H, br s).

Experimental: 13C-NMR (DMSO-d6) δ: 16.6, 26.8, 42.9, 45.5, 50.3, 50.9, 120.9 (J = 12.4 Hz), 127.5, 130.7 (J = 1.7 Hz), 132.2, 132.5 (J = 27.3 Hz), 133.2 (J = 5.0 Hz), 133.3, 149.8 (J = 5.0 Hz), 152.0 (J = 264.0 Hz).

1. Isobe, T.; et. al. Effects of K-115, a rho-kinase inhibitor, on aqueous humor dynamics in rabbits. Curr Eye Res 2014, 39(8), 813-822. (FMO only)
2. Noriaki, G.; et. al. Novel process for the preparation of isoquinoline derivatives or salts thereof. WO2012026529A1