biostudies-literatureOng HWNIH Illuminating the Druggable GenomeUniversity of North CarolinaNIDDK NIH HHSTakeda Pharmaceutical CompanyU.S. Department of DefenseNational Institutes of HealthNorth Carolina Biotechnology CenterNIH HHSNorth Carolina General Assembly12261-12313https://www.ebi.ac.uk/biostudies/studies/S-EPMC11284802biostudies-literatureUnknown67(14)The pyrazolo[1,5-<i>a</i>]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-<i>a</i>]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 <b>53</b>. Despite excellent in vitro metabolic stabilitJournal of medicinal chemistryMore than an Amide Bioisostere: Discovery of 1,2,4-Triazole-containing Pyrazolo[1,5-&lt;i&gt;a&lt;/i&gt;]pyrimidine Host CSNK2 Inhibitors for Combatting β-Coronavirus Replication.PMC11284802S10 OD032476AL1901071U24DK116204-01S10OD032476U24 DK1162042018-IDG-1030Capener JLHavener TMBrown JWDrewry DHOng HWWillson TMDickmander RJAxtman ADYang XTaft-Benz SHowell SMoorman NJKramer ASmith JLCounago RMChang EHeise MSanders MKfalseMore than an Amide Bioisostere: Discovery of 1,2,4-Triazole-containing Pyrazolo[1,5-&lt;i&gt;a&lt;/i&gt;]pyrimidine Host CSNK2 Inhibitors for Combatting β-Coronavirus Replication.The pyrazolo[1,5-<i>a</i>]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-<i>a</i>]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 <b>53</b>. Despite excellent in vitro metabolic stabilit2024-01-01T00:00:00Z2024 Jul2026-06-01T13:27:31.291Z2026-04-08T13:07:16.2ZS-EPMC112848023895945510.1021/acs.jmedchem.4c00962