Discovery of Adamantane Carboxamides as Ebola Virus Cell Entry and Glycoprotein Inhibitors

  • ACS Med Chem Lett. 2020 May 1;11(6):1160-1167. doi: 10.1021/acsmedchemlett.0c00025.
Michael B Plewe  1 ,  Nadezda V Sokolova  1 ,  Vidyasagar Reddy Gantla  1 ,  Eric R Brown  1 ,  Shibani Naik  1 ,  Alexandra Fetsko  1 ,  Donald D Lorimer  2  3 ,  David M Dranow  2  3 ,  Hayden Smutney  2  4 ,  Jameson Bullen  2  3 ,  Rana Sidhu  2  4 ,  Arshil Master  2  4 ,  Junru Wang  2  4 ,  E Adam Kallel  5 ,  Lihong Zhang  6 ,  Birte Kalveram  6 ,  Alexander N Freiberg  6  6 ,  Greg Henkel  1 ,  Ken McCormack  1
Affiliations
  • 1. Arisan Therapeutics, 11189 Sorrento Valley Road, Suite 104, San Diego, California 92121, United States.
  • 2. Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, Washington 98105, United States.
  • 3. UCB Pharma, 7869 NE Day Road West, Bainbridge Island, Washington 98110, United States.
  • 4. UCB Pharma, 3 Preston Court, Bedford, Massachusetts 01730, United States.
  • 5. Victrix, 12631 Bendito Drive, San Diego, California 92128, United States.
  • 6. Department of Pathology andCenter for Biodefense and Emerging Infectious Diseases, The University of Texas Medical Branch, Galveston, Texas 77555, United States.
PMID: 32550996 DOI: 10.1021/acsmedchemlett.0c00025
Abstract

We identified and explored the structure-activity-relationship (SAR) of an adamantane carboxamide chemical series of Ebola virus (EBOV) inhibitors. Selected analogs exhibited half-maximal inhibitory concentrations (EC50 values) of ∼10-15 nM in vesicular stomatitis virus (VSV) pseudotyped EBOV (pEBOV) infectivity assays, low hundred nanomolar EC50 activity against wild type EBOV, aqueous solubility >20 mg/mL, and attractive metabolic stability in human and nonhuman liver microsomes. X-ray cocrystallographic characterizations of a lead compound with the EBOV glycoprotein (GP) established the EBOV GP as a target for direct compound inhibitory activity and further provided relevant structural models that may assist in identifying optimized therapeutic candidates.

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