molecules of the year

MK-0616 is a macrocyclic PCSK9 inhibitor with demonstrated once-daily PCSK9-lowering and LDL-cholesterol-lowering activities in a human clinical trial (<300 mg QD). Currently PCSK9-targeting therapies are only available by injection, and the cost-benefit of using large molecules to lower cholesterol has been hotly debated. Identification of oral PCSK9 inhibitors has been something of a “holy grail” for the field, but difficult to achieve due to the poor ligandability of the target. While MK-0616 has not been formally published, related macrocycles have been disclosed that illustrate the concept. 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 that demonstrated in vivo  target…