Discovery of Novel, Potent Inhibitors of Hydroxy Acid Oxidase 1 (HAO1) Using DNA-Encoded Chemical Library Screening

Inhibition
of hydroxy acid oxidase 1 (HAO1) is a strategy to mitigate
the accumulation of toxic oxalate that results from reduced activity
of alanine–glyoxylate aminotransferase (AGXT) in primary hyperoxaluria
1 (PH1) patients. DNA-Encoded Chemical Library (DECL) screening provided
two novel chemical series of potent HAO1 inhibitors, represented by
compounds 3–6. Compound 5 was further optimized via various structure–activity relationship
(SAR) exploration methods to 29, a compound with improved
potency and absorption, distribution, metabolism, and excretion (ADME)/pharmacokinetic
(PK) properties. Since carboxylic acid-containing compounds are often
poorly permeable and have potential active glucuronide metabolites,
we undertook a brief, initial exploration of acid replacements with
the aim of identifying non-acid-containing HAO1 inhibitors. Structure-based
drug design initiated with Compound 5 led to the identification
of a nonacid inhibitor of HAO1, 31, which has weaker
potency and increased permeability.