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.
| Title: | 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. |
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| Authors: | 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. |
| Source: | Journal of medicinal chemistry [J Med Chem] 2024 Jul 25; Vol. 67 (14), pp. 12261-12313. Date of Electronic Publication: 2024 Jul 03. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural |
| Language: | English |
| Journal Info: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| Imprint Name(s): | Publication: Washington Dc : American Chemical Society; Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| MeSH Terms: | Triazoles*/pharmacology ; Triazoles*/chemistry ; Triazoles*/chemical synthesis ; Pyrimidines*/pharmacology ; Pyrimidines*/chemistry ; Pyrimidines*/chemical synthesis ; Antiviral Agents*/pharmacology ; Antiviral Agents*/chemistry ; Antiviral Agents*/chemical synthesis ; Virus Replication*/drug effects ; Casein Kinase II*/antagonists & inhibitors ; Casein Kinase II*/metabolism; Pyrazoles/pharmacology ; Pyrazoles/chemistry ; Pyrazoles/chemical synthesis ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/chemical synthesis ; Amides/chemistry ; Amides/pharmacology ; Amides/chemical synthesis ; SARS-CoV-2/drug effects ; Animals ; Humans ; Structure-Activity Relationship ; Mice ; Rats ; Drug Discovery ; Male |
| 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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| Grant Information: | S10 OD032476 United States OD NIH HHS; U24 DK116204 United States DK NIDDK NIH HHS |
| Substance Nomenclature: | 0 (Triazoles); 0 (Pyrimidines); 0 (Antiviral Agents); EC 2.7.11.1 (Casein Kinase II); 288-88-0 (1,2,4-triazole); 0 (Pyrazoles); 0 (Protein Kinase Inhibitors); 0 (Amides); 0 (pyrazolo(1,5-a)pyrimidine) |
| Entry Date(s): | Date Created: 20240703 Date Completed: 20240725 Latest Revision: 20250902 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC11284802 |
| DOI: | 10.1021/acs.jmedchem.4c00962 |
| PMID: | 38959455 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural