2. Academic Validation
  3. More than an Amide Bioisostere: Discovery of 1,2,4-Triazole-containing Pyrazolo[1,5- a]pyrimidine Host CSNK2 Inhibitors for Combatting β-Coronavirus Replication

More than an Amide Bioisostere: Discovery of 1,2,4-Triazole-containing Pyrazolo[1,5- a]pyrimidine Host CSNK2 Inhibitors for Combatting β-Coronavirus Replication

  • J Med Chem. 2024 Jul 25;67(14):12261-12313. doi: 10.1021/acs.jmedchem.4c00962.
Han Wee Ong 1 2,  Xuan Yang 1 2,  Jeffery L Smith 2,  Rebekah J Dickmander 1 3 4 5,  Jason W Brown 6,  Tammy M Havener 2,  Sharon Taft-Benz 1 7,  Stefanie Howell 2,  Marcia K Sanders 1 7,  Jacob L Capener 2,  Rafael M Couñago 2 8,  Edcon Chang 6,  Andreas Krämer 9,  Nathaniel J Moorman 1 3 4,  Mark Heise 1 7,  Alison D Axtman 1 2,  David H Drewry 1 2 4,  Timothy M Willson 1 2
Affiliations

Affiliations

  • 1 Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, North Carolina 27599, United States.
  • 2 Structural Genomics Consortium (SGC) and Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 3 Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 4 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 5 Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 6 Takeda Development Center Americas, Inc., San Diego, California 92121, United States.
  • 7 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 8 Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), University of Campinas, Campinas, São Paulo 13083-886, Brazil.
  • 9 SGC, Institute of Pharmaceutical Chemistry, Goethe University Frankfurt am Main, Max-von-Laue-Str. 9, 60438, Frankfurt am Main, Germany.
PMID: 38959455 DOI: 10.1021/acs.jmedchem.4c00962
Abstract

The pyrazolo[1,5-a]pyrimidine scaffold is a promising scaffold to develop potent and selective CSNK2 inhibitors with Antiviral activity against β-coronaviruses. Herein, we describe the discovery of a 1,2,4-triazole group to substitute a key amide group for CSNK2 binding present in many potent pyrazolo[1,5-a]pyrimidine inhibitors. Crystallographic evidence demonstrates that the 1,2,4-triazole replaces the amide in forming key hydrogen bonds with Lys68 and a water molecule buried in the ATP-binding pocket. This isosteric replacement improves potency and metabolic stability at a cost of solubility. Optimization for potency, solubility, and metabolic stability led to the discovery of the potent and selective CSNK2 inhibitor 53. Despite excellent in vitro metabolic stability, rapid decline in plasma concentration of 53 in vivo was observed and may be attributed to lung accumulation, although in vivo pharmacological effect was not observed. Further optimization of this novel chemotype may validate CSNK2 as an Antiviral target in vivo.

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