In humans, inherited deficiency of galactose-1-phosphate uridylyltransferase (GALT) activity can lead to a potentially lethal disease called Classic Galactosemia. Although a galactose-restricted diet prevents the neonatal lethality of this disorder, many well-treated patients continue to develop debilitating complications like mental retardation, neurological deficits, and premature ovarian failure (POF). As elevated level of galactose-1-phosphate (gal-1P), the product of galactokinase (GALK), has long been regarded as the major pathogenic mechanism in Classic Galactosemia, we hypothesize that inhibition of GALK in the patient cells will relieve them from galactose toxicity. Previously, in a high-throughput screen, we identified over 150 small molecule compounds that inhibit human GALK activity in vitro at the level of 86.5% or more. Our SAR studies of selected compounds revealed a lead compound with thiazine structural motif, based on which we synthesized new derivatives for optimized pharmacokinetics. The design, synthesis and evaluation of these new analogs are reported here.

Optimization of human galactokinase (GALK) small molecule inhibitors

241st National Meeting (2011)

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