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

## TL;DR

Researchers optimized a drug candidate for cholesterol-related diseases by improving its stability and effectiveness using a chemical strategy called late-stage functionalization.

## Contribution

The study introduces optimized small-molecule inhibitors of PCSK9 with improved metabolic stability and pharmacological profiles using late-stage functionalization.

## Key findings

- Compounds 6b, 7, and 18a show improved metabolic stability and PCSK9 inhibition compared to the original compound 5c.
- Late-stage functionalization strategies successfully enhanced the drug candidate's pharmacological profile and reduced cytotoxicity.

## 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 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.

Green chemistry‐based late‐stage functionalization (LSF) of the anti‐proprotein convertase subtilisin/kexin type 9 (PCSK9) early lead compound 5c led to optimized analogs with improved metabolic stability/PCSK9 IC50 ratio.© 2026 WILEY‐VCH GmbH