Primary hyperoxalurias (PH) 1-3 are a group of autosomal recessive disorders involving excess hepatic oxalate production and result in frequent kidney stone formation, progressive CKD and in its most severe form, PH1 can lead to ESRD at a young age. Few therapeutic options currently exist for these patients. Lactate dehydrogenase (LDH) catalyzes the final and only committed step in hepatic oxalate synthesis and therefore represents a potential therapeutic target for all forms of PH. Herein we describe the profile of a potent, highly selective small molecule LDH inhibitor which effectively lowers urinary oxalate in a mouse PH1 model and demonstrates an excellent preclinical pharmacokinetic and safety profile. CHK-336 was evaluated in biochemical and cellular LDH activity assays across species and in vivo models of hyperoxaluria, including a novel PH1 mouse generated by Agxt deletion using CRISPR/Cas9. Additional characterization of drug properties, including off-target activities, ADME, safety pharmacology and toxicity in rodents was also performed. CHK-336 demonstrates potent and selective inhibition of LDH in human enzyme assays (IC50 = 0.4 nM) and in cryopreserved hepatocyte assays across species (IC50 = 80 – 131 nM). To minimize the potential for extra-hepatic LDH inhibition, a liver-targeted tissue distribution profile was engineered into the molecule. CHK-336 demonstrates exceptional liver-targeting across species at therapeutic doses (liver/plasma ratio, ~150 (rat, mouse) to >750 (cyno)) and active uptake into rat, cyno and human hepatocytes. Liver targeting is mediated by OATP-uptake into hepatocytes and tight binding to LDH results in a long liver half-life via target-mediated drug disposition that supports once-daily oral dosing. Furthermore, CHK-336 demonstrates a favourable off-target safety and ADME profile with minimal risk of important drug/drug interactions. In the PH1 mouse model, CHK-336 produced significant and dose-dependent reductions in urinary oxalate at low, once-daily oral doses to levels observed in wild-type mice. Wide safety margins were established in rodent toxicity studies to support continued development of CHK-336. By potently blocking LDH, the terminal step in hepatic oxalate synthesis, along with the engineering of a liver-targeted tissue distribution profile, CHK-336 is a promising oral small molecule development candidate with the potential to treat patients with hyperoxaluria.