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

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. Starting from second-generation lead structures such as 2, we were able to refine these structures to obtain extremely potent bi- and tricyclic PCSK9 inhibitor peptides. Optimized molecules such as 44 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 manuscript, we detail the design criteria and multiparameter optimization of this novel series of PCSK9 inhibitors.前蛋白转化酶枯草溶菌素/kexin9型（Proprotein convertase subtilisin-like/kexin type 9，PCSK9）是血浆低密度脂蛋白胆固醇（LDL-cholesterol，LDL-C）的关键调控因子，也是治疗高胆固醇血症与冠状动脉疾病的临床验证靶点。本研究以2等第二代先导化合物为起始结构，对其进行结构优化，得到了活性极强的双环及三环PCSK9抑制肽。优化后的化合物（如化合物44）具备足够的口服生物利用度，经适配制剂给药后，可在大鼠及食蟹猴体内维持治疗浓度。研究证实，该类化合物在食蟹猴体内的靶点结合活性与低密度脂蛋白胆固醇降低效果，与临床获批的注射给药抗体基本一致。本研究首次报道了兼具高活性与口服生物利用度的大环肽类PCSK9抑制剂，其综合特性适于开发为每日一次口服的降脂药物。本文详细阐述了该新型PCSK9抑制剂系列的设计原则与多参数优化过程。