Optimization of 4‐Amino‐2‐Pyridone Inhibitors of Proprotein Convertase Subtilisin/Kexin Type 9: Integrating Structure–Activity and Structure–Metabolism Relationships

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key drug target for the treatment of different hypercholesterolemia-related diseases. A new class of small-molecule inhibitors of PCSK9 transcription, characterized by a 4-amino-2-pyridone scaffold, has been recently identified by our research group. Among them, the early lead compound 5c shows high in vitro potency and favorable in vivo tolerability. However, given the suboptimal in vitro metabolic stability of 5c, its optimization is reported herein by modification of the predicted metabolic soft spots through chemistry-driven late-stage functionalization (LSF) strategies. Microsomal stability on the newly synthesized derivatives allows drawing structure-metabolism relationships (SMRs) that, coupled with a thorough pharmacological investigation on HepG2 cells, leads to the identification of novel C3- and dual C3/NHC4-functionalized pyridones with improved stability and superior pharmacological profiles. Notably, compounds 6b, 7, and 18a emerge as the best candidates, demonstrating markedly improved metabolic stability/PCSK9 IC₅₀ ratio and comparable or lower cytotoxicity with respect to the parent compound 5c. These findings underscore the value of LSF strategies in generating optimized analogs of 5c with strong potential for further preclinical development.