Pyrazole-Based Lactate Dehydrogenase Inhibitors with Optimized Cell Activity and Pharmacokinetic Properties

Lactate dehydrogenase (LDH) catalyzes
the conversion of pyruvate
to lactate, with concomitant oxidation of reduced nicotinamide adenine
dinucleotide as the final step in the glycolytic pathway. Glycolysis
plays an important role in the metabolic plasticity of cancer cells
and has long been recognized as a potential therapeutic target. Thus,
potent, selective inhibitors of LDH represent an attractive therapeutic
approach. However, to date, pharmacological agents have failed to
achieve significant target engagement in vivo, possibly
because the protein is present in cells at very high concentrations.
We report herein a lead optimization campaign focused on a pyrazole-based
series of compounds, using structure-based design concepts, coupled
with optimization of cellular potency, in vitro drug–target
residence times, and in vivo PK properties, to identify
first-in-class inhibitors that demonstrate LDH inhibition in vivo. The lead compounds, named NCATS-SM1440 (43) and NCATS-SM1441 (52), possess desirable attributes for further studying the effect of in vivo LDH inhibition.