A Series of Novel, Highly Potent, and Orally Bioavailable Next-Generation Tricyclic Peptide PCSK9 Inhibitors

Following the first report in the Journal of Medicinal Chemistry in 2020, the IRBM peptide chemistry group is proud to announce a new publication on second generation, potent bi- and tricyclic PCSK9 inhibitor peptides in collaboration with the extraordinary drug discovery team at Merck & co. As a breakthrough in the field of macrocycle drugs, the new optimized molecules demonstrated sufficient oral bioavailability to maintain therapeutic levels in rats and cynomolgus monkeys after dosing with an enabled formulation. These candidates represent the first report of highly potent and orally bioavailable macrocyclic peptide PCSK9 inhibitors with overall profiles favorable for potential development as once-daily oral lipid-lowering agents.