molecules of the month

The Merck bicyclic macrocyclic peptide PCSK9 inhibitor, “compound 44,” is a highly potent (Ki = 0.00239 nM) and orally bioavailable (cyno %F = 2.9, t1/2 = 10 h) agent against a notoriously difficult target for small molecules, demonstrating target engagement comparable to approved PCSK9 antibodies. The discovery of this molecule is an interesting proof of concept for this emerging area of drug space (oral macrocyclic peptides), with hits generated by a relatively new technology (mRNA display screen) and advanced with structure-based design (potency increased by 100,000x). Several off-target issues were addressed while simultaneously lowering clearance, lipophilicity, and improving oral bioavailability. Interestingly, the clearance of the molecules was shifted over time from predominantly hepatic to renal by reducing OATP 1B1 transporter…