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

ABSTRACT: 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 pharmacologica

SUBMITTER: Giannessi L 

PROVIDER: S-EPMC12812009 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature