Small Molecule Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Hit to Lead Optimization of Systemic Agents.
Basic Information
ID: ALA4118248
Journal: J Med Chem
Title: Small Molecule Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Hit to Lead Optimization of Systemic Agents.
Authors: Londregan AT, Wei L, Xiao J, Lintner NG, Petersen D, Dullea RG, McClure KF, Bolt MW, Warmus JS, Coffey SB, Limberakis C, Genovino J, Thuma BA, Hesp KD, Aspnes GE, Reidich B, Salatto CT, Chabot JR, Cate JHD, Liras S, Piotrowski DW.
Abstract: The optimization of a new class of small molecule PCSK9 mRNA translation inhibitors is described. The potency, physicochemical properties, and off-target pharmacology associated with the hit compound (1) were improved by changes to two regions of the molecule. The last step in the synthesis of the congested amide center was enabled by three different routes. Subtle structural changes yielded significant changes in pharmacology and off-target margins. These efforts led to the identification of 7l and 7n with overall profiles suitable for in vivo evaluation. In a 14-day toxicology study, 7l demonstrated an improved safety profile vs lead 7f. We hypothesize that the improved safety profile is related to diminished binding of 7l to nontranslating ribosomes and an apparent improvement in transcript selectivity due to the lower strength of 7l stalling of off-target proteins.
CiteXplore: 29878763
DOI: 10.1021/acs.jmedchem.8b00650
Patent ID: ┄