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.

Autor: Ong HW; Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, North Carolina 27599, United States.; 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., Yang X; Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, North Carolina 27599, United States.; 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., Smith JL; 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., Dickmander RJ; Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, North Carolina 27599, United States.; Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Brown JW; Takeda Development Center Americas, Inc., San Diego, California 92121, United States., Havener TM; 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., Taft-Benz S; Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, North Carolina 27599, United States.; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Howell S; 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., Sanders MK; Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, North Carolina 27599, United States.; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Capener JL; 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., Couñago RM; 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.; Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), University of Campinas, Campinas, São Paulo 13083-886, Brazil., Chang E; Takeda Development Center Americas, Inc., San Diego, California 92121, United States., Krämer A; SGC, Institute of Pharmaceutical Chemistry, Goethe University Frankfurt am Main, Max-von-Laue-Str. 9, 60438, Frankfurt am Main, Germany., Moorman NJ; Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, North Carolina 27599, United States.; Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Heise M; Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, North Carolina 27599, United States.; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Axtman AD; Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, North Carolina 27599, United States.; 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., Drewry DH; Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, North Carolina 27599, United States.; 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.; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Willson TM; Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, North Carolina 27599, United States.; 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.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2024 Jul 25; Vol. 67 (14), pp. 12261-12313. Date of Electronic Publication: 2024 Jul 03.
DOI: 10.1021/acs.jmedchem.4c00962
Abstrakt: 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.
Databáze: MEDLINE
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