BPN-13661

Hearing loss is a major public health concern with no pharmaceutical intervention for hearing protection or restoration. Using zebrafish neuromast hair cells, a robust model for mammalian auditory and vestibular hair cells, we identified a urea-thiophene carboxamide, 1 (ORC-001), as protective against aminoglycoside antibiotic (AGA)-induced hair cell death. The 50% protection (HC₅₀) concentration conferred by 1 is 3.2 μM with protection against 200 μM neomycin approaching 100%. Compound 1 was sufficiently safe and drug-like to validate otoprotection in an in vivo rat hearing loss model. We explored the structure-activity relationship (SAR) of this compound series to improve otoprotective potency, improve pharmacokinetic properties and eliminate off-target activity. We present the optimization of 1 to yield 90 (ORC-13661). Compound 90 protects mechanosensory hair cells with HC₅₀ of 120 nM and demonstrates 100% protection in the zebrafish assay and superior physiochemical, pharmacokinetic, and toxicologic properties, as well as complete in vivo protection in rats.

(1) Aminoglycosides remain indispensable in modern medicine but share a serious dose-limiting adverse effect: irreversible cochleovestibular ototoxicity. (2) This scoping review systematically maps experimental and clinical strategies aimed at preventing aminoglycoside-induced hearing loss, integrating mechanistic insights across preclinical and translational domains. (3) Preclinical evidence, encompassing in vitro and in vivo studies, delineates three principal mechanistic ways of protection: (A) antioxidant and redox modulation, including N-acetyl-L-cysteine (NAC), vitamin C, edaravone, and selected phytochemicals, which counteract reactive oxygen species-mediated hair cell apoptosis; (B) mitochondrial stabilization with compounds such as mitoquinone, celastrol, and histone deacetylase inhibitors restoring bioenergetic and proteostatic balance; and (C) restriction of aminoglycoside entry through partial blockade of the mechano-electrical transduction channel, notably by ORC-13661 and related modulators. Additional strategies involve nitric oxide modulation, vasodilatory agents, and iron chelation. Efficacy, however, remains compound- and antibiotic-specific, with paradoxical effects observed for several drugs. Clinical evidence remains limited and methodologically diverse. Of the investigated pharmacologic interventions, aspirin provides the most robust and reproducible evidence of protection against gentamicin-induced hearing loss, whereas NAC demonstrates a consistent, but population-specific benefit among dialysis patients. In contrast, vitamin E—despite promising experimental findings—has failed to show clinically significant otoprotective effects in randomized human studies. (4) In conclusion, while experimental data establish a strong mechanistic basis for pharmacologic otoprotection, clinical studies remain few, underpowered, and methodologically inconsistent. Standardized, adequately powered, and mechanistically informed clinical trials are urgently needed to translate experimental promise into actionable otoprotective strategies.