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

Sturdivant, J;Williams, SS;Ina, M;Weksler, M;McDougal, A;Clancy, D;deLong, MA;Girouard, N;Zaretskaia, M;Brennan, K;Glendenning, A;Foley, B;Lin, CW;White, JC;Kopczynski, C;Kelly, CR;

Purpose: 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 1.

Methods: Codrugs consisting of a Rho kinase inhibitor (ROCKi) and a corticosteroid were synthesized. Compounds were initially screened in vitro 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 ex vivo corneal metabolism. Lead compound 1 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.

Results: Several ROCK’Sters were found to be potent inhibitors of ROCK (Kis < 50 nM), have high anti-inflammatory activity in vitro (IC50s < 50 nM), display sufficient stability in topical ophthalmic formulations, and have a moderate rate of corneal metabolism. Compound 1 (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 1 (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 1 (0.1%) relative to Lotemax® or vehicle control in an AED mouse model.

Conclusion: ROCK’Ster compound 1 is a novel compound suitable for topical ocular dosing that possesses IOP-lowering capability along with similar anti-inflammatory activity compared with marketed steroids.