Characterization of Hepatotropic Small Molecule Inhibitors of Hypoxia Inducible Factor Prolyl Hydroxylase in the Prevention of Oxygen-Induced Retinopathy

Retinopathy
of prematurity (ROP) blinds severely premature infants
and is caused by oxygen supplementation. Hypoxia-inducible factor
(HIF) stabilization during hyperoxia can prevent oxygen-induced retinopathy
(OIR), the experimental correlate of ROP. Stabilization of hepatic
HIF-1 alone can prevent OIR while contemporaneously protecting other
organ systems, such as the lung and brain, from oxygen toxicity. However,
HIF stabilization in central nervous system (CNS) oligodendrocytes
reduces myelination. Here, we report the synthesis of small molecules
specifically designed to not cross the blood-brain barrier based on
a prodrug structure susceptible to hepatic carboxylesterases that
release active drug. Twenty compounds were synthesized and rank ordered
by Western blot, hypoxia response element binding, and reporter gene
analysis. The lead compound prevented OIR, maintained normal CNS myelination,
preserved the electroretinogram b-wave, and protected astrocytes.
Strategies such as this might be broadly applicable to target specific
hepatic functions while limiting off-target effects in other organs.