PUBLICATION
Phenotypic Optimization of Urea-Thiophene Carboxamides to Yield Potent, Well Tolerated and Orally Active Protective Agents Against Aminoglycoside-Induced Hearing Loss
- Authors
- Chowdhury, S., Owens, K.N., Herr, R.J., Jiang, Q., Chen, X., Johnson, G., Groppi, V.E., Raible, D.W., Rubel, E.W., Simon, J.A.
- ID
- ZDB-PUB-171011-16
- Date
- 2017
- Source
- Journal of medicinal chemistry 61(1): 84-97 (Journal)
- Registered Authors
- Owens, Kelly, Raible, David
- Keywords
- none
- MeSH Terms
-
- Administration, Oral
- Aminoglycosides/adverse effects*
- Animals
- Drug Evaluation, Preclinical
- Hearing Loss/chemically induced*
- Hearing Loss/prevention & control*
- Rats
- Safety*
- Structure-Activity Relationship
- Thiophenes/administration & dosage
- Thiophenes/adverse effects
- Thiophenes/chemistry*
- Thiophenes/pharmacology*
- Urea/chemistry*
- Zebrafish
- PubMed
- 28992413 Full text @ J. Med. Chem.
Citation
Chowdhury, S., Owens, K.N., Herr, R.J., Jiang, Q., Chen, X., Johnson, G., Groppi, V.E., Raible, D.W., Rubel, E.W., Simon, J.A. (2017) Phenotypic Optimization of Urea-Thiophene Carboxamides to Yield Potent, Well Tolerated and Orally Active Protective Agents Against Aminoglycoside-Induced Hearing Loss. Journal of medicinal chemistry. 61(1):84-97.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping