2. Academic Validation
  3. Discovery of Adamantane Carboxamides as Ebola Virus Cell Entry and Glycoprotein Inhibitors

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

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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