2. Academic Validation
  3. Discovery of Broad-Spectrum Herpes Antiviral Oxazolidinone Amide Derivatives and Their Structure-Activity Relationships

Discovery of Broad-Spectrum Herpes Antiviral Oxazolidinone Amide Derivatives and Their Structure-Activity Relationships

  • ACS Med Chem Lett. 2024 Jul 9;15(8):1232-1241. doi: 10.1021/acsmedchemlett.4c00117.
Michael A Plotkin 1,  Marc Labroli 1,  Jeffrey Schubert 1,  Anthony Shaw 1,  Kelly-Ann S Schlegel 1,  Richard Berger 1,  Andrew J Cooke 2,  Robert P Hayes 3,  Kira A Armacost 4,  Keith Kinek 5,  Paula Krosky 6,  Christine Burlein 6,  Shi Meng 6,  Edward DiNunzio 7,  Edward M Murray 5,  Sony Agrawal 7,  Maria Madeira 8,  Amy Flattery 9,  Huifang Yao 8,  Andrew Leithead 10,  William A Rose 2nd 9,  Christopher Cox 1,  David M Tellers 1,  Philip M McKenna 5,  Izzat Raheem 1
Affiliations

Affiliations

  • 1 Discovery Chemistry, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
  • 2 Medicinal Chemistry, Exscientia, 53 State Street, Boston, Massachusetts 02109, United States.
  • 3 Protein and Structural Chemistry, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
  • 4 Computational Sciences, GlaxoSmithKline, Collegeville Pennsylvania 19426, United States.
  • 5 Discovery Biology, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
  • 6 In Vitro Pharmacology, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
  • 7 Quantitative Biosciences, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
  • 8 Discovery Pharmaceutical Sciences, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
  • 9 In Vivo Pharmacology, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
  • 10 Discovery Pharmaceutical Sciences, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
PMID: 39140041 DOI: 10.1021/acsmedchemlett.4c00117
Abstract

Herpesvirus infections are ubiquitous, with over 95% of the adult population infected by at least one strain. While most of these infections resolve without treatment in healthy individuals, they can cause significant morbidity and mortality in immunocompromised, stem cell, or organ transplant patients. Current nucleoside standards of care provide meaningful benefit but are limited due to poor tolerability, resistance, and generally narrow spectrum of activity. Herpesviruses share a conserved DNA Polymerase, the inhibition of which is validated as an effective strategy to disrupt viral replication. By utilizing a non-nucleoside inhibitor of the viral DNA Polymerase, we sought to develop agents covering multiple herpesviruses (e.g., CMV, VZV, HSV1/2, EBV, and HHV6). Herein is described the invention of an Oxazolidinone class of broad-spectrum non-nucleoside herpes Antiviral inhibitors. A lead compound (42) with potent biochemical and broad-spectrum cellular activity was found to be efficacious in murine models against both HSV-1 and CMV Infection.

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