Galactosemia is a rare genetic metabolic disorder that affects an individual’s ability to metabolize the sugar galactose properly. And it is mainly caused by deficient galactose-1 phosphate uridylyltransferase (GALT). As a result of GALT deficiency, galactose-1 phosphate (gal-1P) produced by galactokinase (GALK1, gene code GALK1) accumulates, and UDP-galactose and UDP-glucose become deficient in cells. Accumulation of galactose-1 phosphate is thought to be the major cause of the chronic complications associated with this disease, which currently has no treatment. Inhibition of GALK1 is a novel strategy for the treatment of classical galactosemia.
NCATS-SM4487 is a highly selective unique dihydropyrimidine inhibitor against galactokinase (GALK1). And the GALK1 is an enzyme that generates galactose-1 phosphate. Therefore, NCATS-SM4487 prevents galactose-1 phosphate (gal-1P) accumulation at low micromolar concentrations. In fibroblasts, NCATS-SM4487 reduces gal-1P/protein levels in dose dependence. In addition, NCATS-SM4487 shows moderate stability in mouse liver microsomes (MLMs). For preliminary pharmacokinetic (PK) experiments in female CD1 mice, a single-dose 3 mg/kg IV study indicates a Co of 8.25 μM drug concentration in plasma with a short half-life of ∼0.4 h. A 30 mg/kg PO study leads to a Cmax of 7.02 μM and AUCinf of 15.96 h·μM with a bioavailability of 33%. Moreover, a single 50 mg/kg intraperitoneal (IP) dose and found favorable plasma concentrations above 1 μM up to ∼7 h after dosing. Certainly, NCATS-SM4487 shows 98.74% protein binding in mixed-gender CD-1 mouse plasma. Thus, NCATS-SM4487 has the potential for galactosemia research.
To sum up, NCATS-SM4487 is a highly selective GALK1 inhibitor, an has the potential for galactosemia research.
 Li Liu, et al. J Med Chem. 2021 Sep 23;64(18):13551-13571.