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Phenotypic Optimization of Urea–Thiophene Carboxamides To Yield Potent, Well Tolerated, and Orally Active Protective Agents against Aminoglycoside-Induced Hearing Loss

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    Phenotypic Optimization of Urea–Thiophene Carboxamides To Yield Potent, Well Tolerated, and Orally Active Protective Agents against Aminoglycoside-Induced Hearing Loss
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    † ○ ¶ †Clinical Research, ○Human Biology, and Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, United States
    ‡ Virginia Merrill Bloedel Hearing Research Center, University of Washington, Seattle, Washington 98195, United States
    § AMRI, Albany, New York 12203, United States
    ∥ NuPharmAdvise LLC, Sanbornton, New Hampshire 03269 United States
    ⊥ Oricula Therapeutics, Seattle, Washington 98154, United States
    # Center for Discovery of New Molecules, University of Michigan, Ann Arbor, Michigan 48109, United States
    ∇ Department of Biological Structure, University of Washington, Seattle, Washington 98195, United States
    *Phone: 206-667-6241. Fax: 206-667-5255. E-mail: [email protected]
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2018, 61, 1, 84–97
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    https://doi.org/10.1021/acs.jmedchem.7b00932
    Published October 9, 2017
    Copyright © 2017 American Chemical Society
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    Abstract

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    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.

    Copyright © 2017 American Chemical Society

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    (PDF) (CSV) The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.7b00932.

    • Reproducibility of zebrafish lateral line hair cells viability assay, pharmacokinetic and toxicological properties of 90, compound 90 crystal structure determination, noninterference in antimicrobial activity of aminoglycoside antibiotics, full experimental procedures, and characterization of compounds 1–99 (PDF)

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    X-ray crystallographic structure of 90 HCl has been deposited at The Cambridge Crystallographic Database (CSD) with the accession code CCDC-1557948 (http://ccdc.cam.ac.uk).

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    Cited By

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    This article is cited by 51 publications.

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2018, 61, 1, 84–97
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.7b00932
    Published October 9, 2017
    Copyright © 2017 American Chemical Society
    Request reuse permissions

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