Kinetics of the acid hydrolysis of uridine diphosphate glucose and 3-N-methyluridine diphosphate glucose

Covalent Guanosine Mimetic Inhibitors of G12C KRAS

“…A diphosphate compound, SML-8-73-1 suffers from chemical and enzymatic instability, given that the phosphate anhydride bond is prone to hydrolysis . This is problematic from two perspectives: first, unstable compounds are inherently disadvantageous from a pharmacokinetic perspective; and second, a caging strategy will likely be required to shield charged atoms in the phosphate pharmacophore to enhance cell permeability, and the resulting steric bulk may further destabilize the phosphate anhydride bond.…”

“…A diphosphate compound, SML-8-73-1 suffers from chemical and enzymatic instability, given that the phosphate anhydride bond is prone to hydrolysis. 24 This is problematic from two perspectives: first, unstable compounds are inherently disadvantageous from a pharmacokinetic perspective; and second, a caging strategy will likely be required to shield charged atoms in the phosphate pharmacophore to enhance cell permeability, and the resulting steric bulk may further destabilize the phosphate anhydride bond. To address these potential issues, the central oxygen was substituted with a methylene group.…”