Gram-Scale Synthesis of an Arylsulfonamide-Type Alkaline Phosphatase Inhibitor.

Alkaline phosphatases (ALP) are present in most living organisms. This family of metalloenzymes catalyzes transphosphorylation reactions and hydrolyzes phosphate monoesters. ALP enzymes have significant roles in several physiological processes and disease states. Inhibition of these enzymes makes it possible to prevent or treat certain diseases, and their role in normal physiology can also be examined. Several inhibitors with diverse chemical structures have been reported. One of them, known as SBI-425, has a low IC50 value (16 nM). An alternative, scalable method was established to prepare SBI-425 in larger amounts for in vivo experiments. In three simple steps, 4-chloroanisole was transformed to the appropriate sulfonyl chloride, which was used to acylate 3-aminonicotinamide. Without the need for chromatography or crystallization, the desired inhibitor was obtained with >90% purity (based on UPLC-MS analysis). The synthesis could also be carried out on a 10-fold scale, with identical outcomes. The final product was subjected to biological testing, and it was found to be effective in inhibiting ALP activity in mouse serum.