Small Molecule Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Hit to Lead Optimization of Systemic Agents

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.