%0 Journal Article
%A Chowdhury, Sarwat
%A N. Owens, Kelly
%A Herr, R. Jason
%A Jiang, Qin
%A Chen, Xinchao
%A Johnson, Graham
%A Groppi, Vincent E.
%A W. Raible, David
%A Rubel, Edwin W
%A Simon, Julian A.
%D 2017
%T Phenotypic Optimization
of Urea–Thiophene Carboxamides
To Yield Potent, Well Tolerated, and Orally Active Protective Agents
against Aminoglycoside-Induced Hearing Loss
%U https://acs.figshare.com/articles/journal_contribution/Phenotypic_Optimization_of_Urea_Thiophene_Carboxamides_To_Yield_Potent_Well_Tolerated_and_Orally_Active_Protective_Agents_against_Aminoglycoside-Induced_Hearing_Loss/5545345
%R 10.1021/acs.jmedchem.7b00932.s001
%2 https://acs.figshare.com/ndownloader/files/9605086
%K 3.2 μ M
%K AGA
%K SAR
%K 200 μ M neomycin
%K HC 50
%K mechanosensory hair cells
%K vestibular hair cells
%K protection
%K zebrafish neuromast hair cells
%K Aminoglycoside-Induced Hearing Loss Hearing loss
%K pharmacokinetic
%K ORC
%K vivo rat hearing loss model
%X 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.
%I ACS Publications