Abstract
Purpose :
Traumatic optic neuropathy (TON) is a cause of visual loss after blunt or penetrating head trauma. B-3(+) is a fluorenone compound that has demonstrated significant efficacy in preventing mortality in the animal models of concussive brain injury. B-3(+) acts as a non-diuretic small molecule anion transport inhibitor capable of engaging several molecular targets. Given the efficacy of B-3(+) in animal models of traumatic brain injury and assuming that mechanisms of neuronal damage in the canalicular portion of the optic nerve are analogues to those of the rest of the CNS, we hypothesized that intravitreally administered B-3(+) may be used as a treatment for TON. To advance B-3(+) characterization, we describe here the evaluation of its vitro ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties.
Methods :
Characterization of B-3(+) was performed in the following assays: solubility, CYP inhibition, metabolic stability in liver microsomes, plasma protein binding, MDR1-MDCK permeability, hERG inhibition, hepatic intrinsic clearance and hepatocyte stability, CYP phenotyping, and CYP induction
Results :
B-3(+) has optimal drug-like characteristics and demonstrates very good solubility, optimal metabolic stability, and no significant CYP inhibition. No ADMET attributes that could prevent the development of B-3(+) as an intravitreally administered therapy for TON were revealed in our studies.
Conclusions :
In vitro ADMET characteristics determined for B3(+) in conducted studies justify additional characterization of this compound as a potential treatment for traumatic optic neuropathy.
This is a 2020 ARVO Annual Meeting abstract.