A digoxin derivative that potently reduces intraocular pressure - efficacy and mechanism of action in different animal models

Am J Physiol Cell Physiol. 2024 Apr 1. doi: 10.1152/ajpcell.00617.2023. Online ahead of print.ABSTRACTGlaucoma is a blinding disease. Reduction of intraocular pressure (IOP) is the mainstay of treatment, but current drugs show side-effects or become progressively ineffective, highlighting the need for novel compounds. We have synthesized a family of perhydro-1,4-oxazepine derivatives of digoxin, the selective inhibitor of Na,K-ATPase. The cyclobutyl derivative (DcB) displays strong selectivity for the human a2 isoform and potently reduces IOP in rabbits. These observations appeared consistent with a hypothesis that in ciliary epithelium DcB inhibits the a2 isoform of Na,K-ATPase, which is expressed strongly in non-pigmented cells, reducing aqueous humor (AH) inflow. This paper extends assessment of efficacy and mechanism of action of DcB using an ocular hypertensive non-human primate model (OHT-NHP) (Macaca fascicularis). In OHT-NHP, DcB potently lowers IOP, in both acute (24 hour) and extended (7-10 day) settings, accompanied by increased aqueous humor flow rate (AFR). By contrast, ocular normotensive animals (ONT-NHP) are poorly responsive to DcB, if at all. The mechanism of action of DcB has been analyzed using isolated porcine ciliary epithelium and perfused enucleated eyes to study AH inflow and AH outflow facility, respectively. (1) DcB significantly stimulates AH inflow although prior addition of 8-Br-cAMP, which raises AH inflow, precludes additional effects of DcB. (...

Source: Am J Physiol Cell Ph... - April 1, 2024 Category: Cytology Authors: Veluchamy Amutha Barathi Adriana Katz Shashikant Chaudhary Hoi-Lam Li Daniel M Tal Arie L Marcovich Chi-Wai Do Steven J D Karlish Source Type: research