Ocular Pharmacokinetics of a Novel Class of Selective Multi-Kinase Inhibitors with Anti-Inflammatory Potential

Abstract

Purpose : Inflammatory mediators have been implicated in multiple ocular disorders such as neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), non-infectious uveitis, and dry eye. Therefore, inhibiting pro-inflammatory kinases such as Janus kinases (JAKs) and/or nuclear factor kappa-B kinase subunit beta (IKK-B) holds promise as potential therapeutic strategies for ocular indications. We have generated a novel class of selective multi-kinase inhibitors that have varying levels of activity against JAKs, IKK-B, and Rho kinase (ROCK). ROCK is associated with inflammation-mediated pathways, as well as in vascular growth, blood vessel barrier function and fibrosis. Therefore, the concomitant inhibition of these multiple kinases has the potential to produce better outcomes in multiple ocular disorders. In this study, we report the ocular pharmacokinetics of Compound 1, a member of this novel class of inhibitors that targets JAK2, JAK3, IKK-B, ROCK1 and ROCK2.

Methods : Inhibitory activity of Compound 1 was determined in vitro against JAK2, JAK3, IKK-B, ROCK1 and ROCK2 in ATP-binding assays. Cellular assays were also conducted to confirm inhibition of these intracellular targets as well as its potential for toxicity. The ocular distribution of Compound 1 was investigated following intraperitoneal (ip) and topical administration in mice. The tissue levels of Compound 1 in the cornea, conjunctiva, retina, Meibomian glands and lacrimal glands were determined by LC/MS/MS analysis.

Results : Compound 1 has nanomolar activity against JAK2, JAK3, IKK-B, ROCK1, and ROCK2 in ATP binding assays. It has a low toxicity profile in cellular assays (LC₅₀ > 70 mM). Following both ip injections and topical drops, Compound 1 was found in ocular surface tissues as well as in the retina at physiologically relevant levels.

Conclusions : We have developed a novel class of selective multi-kinase inhibitors with varying degrees of activity against JAK2, JAK3, IKK-B, ROCK1 and ROCK2. In this study, we demonstrated favorable pharmacokinetic properties in ocular tissues with Compound 1. We are currently assessing the efficacy of these novel compounds in various models of ocular diseases.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.