Proprotein convertase subtilisin-like/kexin type 9, PCSK9, is a key regulator of plasma LDL-cholesterol, LDL-C, and a clinically validated target for the treatment of hypercholesterolemia and coronary artery disease. A series of novel cyclic peptide hits derived from an mRNA display screen were optimized to achieve picomolar level binding peptides through stabilization and rigidificaton of the structure driven by structure-based drug design approach. After metabolic stabilization of both protease degradation and transportater mediated hepatic uptake, optimized molecules demonstrated sufficient oral bioavailability to maintain therapeutic levels in rats and cynomolgus monkeys after dosing with an enabled formulation.

We demonstrated target engagement and LDL lowering in cynomolgus monkeys essentially identical to those observed with the clinically approved, parenterally dosed antibodies. These molecules 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.

In this talk, we detail the design criteria and multiparameter optimization of this novel series of PCSK9 inhibitors.