Cardiovascular

Cell culture and mouse studies identified a pyrimidinone-based inhibitor of TLR4 that could help treat MI. Chemical synthesis and screening of peptidomimetic analogs of a previously identified TLR4 inhibitor peptide in cardiomyocytes cultured under hypoxic conditions yielded a pyrimidinone-based compound that decreased levels of the myocardial injury markers creatine kinase MB and lactate dehydrogenase (LDH) compared with vehicle. In a mouse model of MI, the compound decreased infarct size and serum levels of creatine kinase MB, LDH and the myocardial injury marker troponin and increased survival. In silico docking of the compound with TLR4 identified a binding pocket for the compound in the intracellular domain of TLR4, suggesting TLR4 as the compound’s probable target. Next steps include PK and toxicity testing of the compound.

Eisai Co. Ltd. has eritoran (E5564), a synthetic lipid A analog that blocks TLR4 activation, in Phase III testing for severe sepsis...