In vitro activity and ocular pharmacokinetics (PK) of SF0166, a topically administered α_v integrin antagonist

Abstract

Purpose : Small molecule antagonists of α_vβ₃ and α_vβ₅ inhibit retinal neovascularization after intraperitoneal or periocular injection. We evaluated the in vitro anti-adhesion and anti-angiogenic activity of SF0166, a small molecule α_vβ₃ antagonist, as well as ocular PK after topical administration in an ophthalmic solution.

Methods : SF0166 was assessed for binding to α_vβ₃, α_vβ₅, α_vβ₆, and α_vβ₈ integrins. The ability of SF0166 to block adhesion to vitronectin and fibronectin was tested (L-000845704 positive control). Anti-angiogenic activity was tested in chick chorioallantoic membrane (CAM) assays (staurosporine positive control). Ocular uptake and tissue distribution was assessed after a single topical ocular administration of 5% SF0166 (2.5 mg/eye) to Dutch-Belted rabbits (3 animals [6 eyes]/timepoint).

Results : SF0166 inhibited human integrin-ligand interactions at IC₅₀ values of 0.6 nM for α_vβ₃, 8 nM for α_vβ₆, and 13 nM for α_vβ₈; SF0166 did not inhibit binding to α_vβ₅. SF0166 was a potent inhibitor of cell adhesion to vitronectin and substantially less potent for fibronectin (Table 1). In the CAM assay, angiogenesis stimulated by bFGF was inhibited in a dose-dependent manner (36% reduction in vessel score at 0.5 μg, 42% at 1 μg, 58% at 4 μg vs 67% for 1 µg staurosporine). Angiogenesis stimulated by VEGF was inhibited in a potent dose-dependent manner (61% at 2 μg; 88% at 5 μg vs 90% for 1 µg staurosporine). Angiogenesis stimulated by PDGF was moderately inhibited with no clear dose response. SF0166 distributed to the choroid and retina after topical ocular administration in amounts that substantially exceeded the cellular IC₅₀ for adhesion to vitronectin; drug concentrations were maintained for >12 hours (Table 2). The concentration of SF0166 in the retina-choroid peaks at 4438 ng/g or 7.8 nmol/g (formula weight of SF0166 is 565 g/mol), or ~8 μM (assuming a tissue density of 1 g/mL).

Conclusions : SF0166 resulted from a drug discovery effort to synthesize small molecule α_vβ₃ antagonists with physiochemical properties that distribute to the posterior segment of the eye after topical administration in an ophthalmic solution. The high levels of SF0166 in the sclera and low levels in the vitreous show a scleral route of distribution to the back of the eye.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.