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A series of trisubstituted hydroxylactams was identified as potent enzymatic and cellular inhibitors of human lactate dehydrogenase A. Utilizing structure-based design and physical property optimization, multiple inhibitors were discovered with &lt;10 μM lactate IC 50 in a MiaPaca2 cell line. Optimization of the series led to 29 , a potent cell active molecule (MiaPaca2 IC 50 = 0.67 μM) that also possessed good exposure when dosed orally to mice.

Cell Active Hydroxylactam Inhibitors of Human Lactate Dehydrogenase with Oral Bioavailability in Mice