Novel corticosteroids with inhibitory activity against ROCK reach target ocular tissues and reduce inflammation in EIU

Abstract

Purpose : The anti-inflammatory efficacy of corticosteroids is unmatched and widely utilized in ocular indications. However, risks to steroid use are significant and include steroid-induced ocular hypertension/glaucoma, which is thought to develop as extracellular matrix proteins accumulate and impair proper function of the trabecular meshwork (TM). Rho kinase (ROCK) inhibition has been shown to attenuate steroid-induced collagen and fibronectin deposition in cultured TM cells. Furthermore, ROCK inhibition has been shown to lower IOP by increasing aqueous outflow through the TM. Inhibition of ROCK in conjunction with steroid use for ocular inflammatory conditions may provide a strategy to decrease the risk for steroid-induced glaucoma. We describe the generation of novel corticosteroids covalently linked to ROCK inhibitor compounds and report their tissue distribution following topical dosing as well as their anti-inflammatory efficacy in the mouse endotoxin-induced uveitis (EIU) model.

Methods : Over 50 novel compounds containing a steroid linked to a ROCK inhibitor were synthesized. Dexamethasone, prednisolone, fluocinolone, and triamcinolone were linked to various ROCK inhibitors including the active metabolite of netarsudil, AR-13503. Ocular tissue distribution following topical administration was assessed by mass spectrometry. Anti-inflammatory efficacy was determined in the EIU model following topical instillation.

Results : Following topical dosing with the ROCK-steroids, the steroid and the ROCK-inhibitor metabolites are found in various ocular tissues. Low doses of these novel compounds reduce inflammation in EIU to levels comparable to clinically relevant treatments today.

Conclusions : Covalently linked ROCK-steroid compounds retain their anti-inflammatory efficacy. The potential for these compounds to provide lower risk profiles than conventional corticosteroids deserves further investigation.

This is a 2020 ARVO Annual Meeting abstract.