(265) Quinoxaline in Auditory Hair Cell Regeneration

Objective : Sensory hair cells (HC), the mechanoreceptors of the auditory and vestibular systems, are crucial for hearing and balance. Post-mitotic mammalian HCs do not regenerate after traumatic damage, and their death leads to irreversible hearing and balance impairment. To date, there are no available FDA-approved pharmacologic alternatives or methods to trigger HC regeneration safely with potential to treat hearing loss. Our group has uncovered the proliferative potential of quinoxaline (Qx), a non-steroidal anti-inflammatory benzopyrazine compound, to regenerate lost HCs. Qx is a low molecular weight (MW = 130.15 g/mol) compound and structure activity relationships (SAR) have yet to be determined. We hypothesize that novel Qx analogs will expand SAR of this novel chemotype, improve HC proliferation, optimized ADMETox profiles, and achieve in vivo efficacy.

Methods: During the past three years, we synthesized a series of Qx-analogs to expand the SAR of this novel chemotype and identify other proliferative analogs focused potency optimization, improved bioavailability, and in vivo efficacy to regenerate lost HCs. We synthesized substituted 2-aminobenzopyrizines in good yields, characterized by 1H NMR and mass spectrometry. Our efforts have yielded two lead analogs,

Results: Our efforts have yielded two lead analogs, Qx-294 and Qx-301, which have enhanced proliferative HC action and show promising in vitro ADMETox profiles, supporting good bioavailability and safe pharmacological profile. Both compounds have been shown to have rapid absorption in zebrafish and induce supporting cell (SC) proliferation in vitro (HEI-OC1 cells, cochleae explants) and in vivo (zebrafish neuromast and mouse inner ear) without signs of apoptosis.

Conclusions: We conclude that Qx and novel Qx analogs (Qx-294 and Qx-301) have strong translational potential to prevent and/or treat hearing loss supporting further development of this series.