Ripasudil free base (K-115 (free base)) is a selective and potent ROCK inhibitor, is a novel and potent antiglaucoma agent.

PKACa:2.1 μM, PKC:27 μM, ROCK2:19 nM, CaMK IIa:370 nM, ROCK1:51 nM

Ripasudil 显著降低了房水中的浸润细胞和蛋白质渗出量，以及ICB中浸润细胞数量和视网膜血管中粘附性白细胞的数量。此外，Ripasudil 还抑制了房水中MCP-1蛋白水平和ICB及视网膜中IL-1β、IL-6、TNF-α、MCP-1及细胞间黏附分子-1的mRNA水平。Ripasudil还抑制了RAW264.7细胞中MCP-1的产生和NF-κB的核转移。

Ripasudil对ROCKs有选择性和强大的抑制作用。在兔子上，点眼Ripasudil能够以剂量依赖的方式显著降低眼内压力（IOP），最大眼内压力降低发生在点眼后1小时，降低幅度为8.55 ± 1.09 mmHg（平均值 ± 标准误），使用浓度为0.5%。在猴子中，最大眼内压力降低观察到在点眼后2小时，降低幅度为4.36 ± 0.32 mmHg，使用浓度为0.4%，比0.005%的latanoprost的效果显著更强。全头自显影显示，在点眼[(14)C]Ripasudil后15分钟，在同侧眼里的放射性水平最高。在兔子中，0.4% Ripasudil的单次点眼未对房水流速或葡萄膜静脉流出有影响，但与对照组眼睛相比，显著增加了常规流出设施的2.2倍。

Endotoxin-induced uveitis was induced by footpad injection of lipopolysaccharide (LPS). Ripasudil was administered intraperitoneally 1 hour before and after LPS injection. The aqueous humor was collected 24 hours after injection, and the infiltrating cells, protein concentration, and levels of monocyte chemotactic protein-1 (MCP-1) were determined. Infiltrating cells in the iris ciliary body (ICB) and adherent leukocytes in retinal vessels were evaluated. The mRNA levels of IL-1β, IL-6, TNF-α, and MCP-1 in the retina and ICB were determined. A mouse macrophage cell line, RAW264.7, was stimulated with LPS in the presence or absence of ripasudil, and the expression of MCP-1 and nuclear translocation of nuclear factor (NF)-κB was analyzed[1].

Kinase inhibition by K-115 was measured by biochemical assay.?IOP was monitored using a pneumatonometer in albino rabbits and monkeys after topical instillation of K-115.?The ocular distribution of [(14)C]K-115 was determined by whole-head autoradiography.?The aqueous flow rate was determined by fluorophotometry.?The total outflow facility and uveoscleral outflow were measured by two-level constant pressure perfusion and perfusion technique using fluorescein isothiocyanate-dextran, respectively[2].