J Med Chem. 2026 Jan 30. doi: 10.1021/acs.jmedchem.5c01451. Online ahead of print.
ABSTRACT
Trimethylamine (TMA) Lyase is an enzyme expressed in human gut bacteria that plays a pivotal role in the formation of trimethylamine oxide (TMAO), a metabolite implicated in the development of heart failure. Here, we describe a strategy to design covalent inhibitors targeting the active site thiyl radical involved in the catalytic cycle of the enzyme under anaerobic conditions. This strategy led to the discovery of 7, a previously unreported highly potent and selective inhibitor of TMA Lyase. When dosed orally to rats, 7 shows a significant reduction of circulating TMAO levels and, importantly, demonstrates inhibition of TMAO generated from a human microbiome when profiled in a human fecal mouse transplant model.
PMID:41614677 | DOI:10.1021/acs.jmedchem.5c01451