Discovery and Preclinical Development of Novel Intraocular Pressure-Lowering Rho Kinase Inhibitor: Corticosteroid Conjugates

• Published in: Journal of ocular pharmacology and therapeutics Vol. 39; no. 2; p. 117
• Main Authors: Sturdivant, Jill, Williams, Stuart S, Ina, Maria, Weksler, Meredith, McDougal, Alan, Clancy, Daphne, deLong, Mitchell A, Girouard, Natalie, Zaretskaia, Maria, Brennan, Karen, Glendenning, Angela, Foley, Briana, Lin, Cheng-Wen, White, Jeffrey C, Kopczynski, Casey, Kelly, Curtis R
• Format: Journal Article
• Language: English
• Published: United States 01.03.2023
• Subjects: Adrenal Cortex Hormones; Animals; Antihypertensive Agents; Cornea; Disease Models, Animal; Eye Diseases - drug therapy; Intraocular Pressure; Mice; Ophthalmic Solutions - pharmacology; Rabbits; rho-Associated Kinases; corticosteroid; Rho kinase; intraocular pressure; cataract surgery; glaucoma
• ISSN: 1557-7732
• DOI: 10.1089/jop.2022.0129

A new class of ocular steroids designed to mitigate steroid-induced intraocular pressure (IOP) elevation while maintaining anti-inflammatory activity was developed. Herein is described the discovery and preclinical characterization of ROCK'Ster compound . Codrugs consisting of a Rho kinase inhibitor (ROCKi) and a corticosteroid were synthesized. Compounds were initially screened for ROCKi activity and anti-inflammatory activity against the proinflammatory interleukin 23 and bacterial lipopolysaccharide (LPS) pathways. Selected compounds were then screened for solubility, chemical stability, and corneal metabolism. Lead compound was evaluated for IOP lowering in the Dutch Belted rabbit and for anti-inflammatory efficacy in both a postcataract surgery model and an allergic eye disease (AED) mouse model. Several ROCK'Sters were found to be potent inhibitors of ROCK ( s < 50 nM), have high anti-inflammatory activity (IC s < 50 nM), display sufficient stability in topical ophthalmic formulations, and have a moderate rate of corneal metabolism. Compound (0.1% and 0.25%, quater in die [QID]-4 times a day) demonstrated IOP-lowering capability without inducing hyperemia in our rabbit model. When compared with the marketed steroids, Durezol and Pred Forte , compound (0.1%, 0.25%) demonstrated noninferiority in clinical scoring in a rabbit model of inflammation after surgery. In addition, anti-inflammatory outcomes were observed with compound (0.1%) relative to Lotemax or vehicle control in an AED mouse model. ROCK'Ster compound is a novel compound suitable for topical ocular dosing that possesses IOP-lowering capability along with similar anti-inflammatory activity compared with marketed steroids.