Esther C. Y. Lee; Andrew J. McRiner; Katy E. Georgiadis; Julie Liu; Zooey Wang; Andrew D. Ferguson; Benjamin Levin; Moritz von Rechenberg; Christopher D. Hupp; Michael I. Monteiro; Anthony D. Keefe; Allison Olszewski; Charles J. Eyermann; Paolo Centrella; Yanbin Liu; Shilpi Arora; John W. Cuozzo; Ying Zhang; Matthew A. Clark; Christelle Huguet; Anna Kohlmann
J. Med. Chem., 2021, 64(10), 6730–6744
https://doi.org/10.1021/acs.jmedchem.0c02271

Abstract

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.